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Contents lists available at SciVerse ScienceDirect
Journal of Steroid Biochemistry and Molecular Biology
jo urnal homepage: www.elsevier.com/locate/jsbmb
1 Review
2 Current status on development of steroids as anticancer agents
∗
3 Q1 Atul Gupta, B. Sathish Kumar, Arvind S. Negi
4 Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, Lucknow 226015, U.P., 5 India
6
a r t a b
7 i c l e i n f o s t r a c t
8
9 Article history: Steroids are important biodynamic agents. Their affinities for various nuclear receptors have been an
10 Received 4 December 2012
interesting feature to utilize them for drug development particularly for receptor mediated diseases.
11 Received in revised form 25 April 2013
Steroid biochemistry and its crucial role in human physiology, has attained importance among the
12 Accepted 19 May 2013
researchers. Recent years have seen an extensive focus on modification of steroids. The rational mod-
13
ifications of perhydrocyclopentanophenanthrene nucleus of steroids have yielded several important
14 Keywords:
anticancer lead molecules. Exemestane, SR16157, fulvestrant and 2-methoxyestradiol are some of the
15 Antiestrogens
successful leads emerged on steroidal pharmacophores.
16 Aromatase inhibitors
The present review is an update on some of the steroidal leads obtained during past 25 years. Various
17 Hormone dependent cancers
steroid based enzyme inhibitors, antiestrogens, cytotoxic conjugates and steroidal cytotoxic molecules
18 17-Hydroxysteroids dehydrogenase
19 inhibitors of natural as well as synthetic origin have been highlighted.
20 Steroid conjugates This article is part of a Special Issue entitled ‘Synthesis of steroids’.
21 Steroid sulfatase inhibitors © 2013 Published by Elsevier Ltd.
22 Contents
23 1. Introduction ...... 00
24 2. Steroids as antiproliferative agents ...... 00
25 2.1. Enzyme inhibitors ...... 00
26 2.1.1. Steroid sulfatase inhibitors ...... 00
27 2.1.2. Aromatase inhibitors ...... 00
28 2.1.3. 17-Hydroxysteroid dehydrogenase inhibitors ...... 00
29 2.2. Antiestrogens ...... 00
30 2.3. Antiprogestins ...... 00
31 3. Steroids as cytotoxic agents ...... 00
32 4. Conclusions ...... 00
33 Conflict of interest ...... 00
34 Acknowledgement ...... 00
35 References ...... 00
3736
of time, these can move from one organ to another through the 45
38 1. Introduction
blood and lymph systems and damage the healthy cells in differ- 46
39 Carcinogenesis is a highly complex multistep process induced ent tissues. This stage of disease is known as metastasis. Because of 47
40 by a number of carcinogens which leads to development of can- the severity of disease, cancer is now considered one of the social 48
41 cer [1]. Depending upon stage of disease and affected body part, and economic concerns on the public health-care system. Over the 49
42 there are more than 100 different types of cancer such as oral, years, several anticancer drugs have been developed with excel- 50
43 lung, breast, uterine and ovary. Cancer cells abnormally divide lent cytotoxicity such as paclitaxel and cisplatin. However, owing 51
44 without control and invade nearby normal cells. Over the period to their non-selective action these are associated with serious side 52
effects such as bone marrow depression, alopecia and nephrotoxic- 53
ity. Hence, their use is limited. On the other hand, antiproliferative 54
∗ drug like tamoxifen have receptor based high selective action on 55
Corresponding author. Tel.: +91 522 2342676x327; fax: +91 522 2342666.
cancer cells. However, these agents are not very effective to kill the 56
E-mail addresses: [email protected], [email protected]
(A.S. Negi). existing tumour cells and their prolong use may develop uterine 57
0960-0760/$ – see front matter © 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.jsbmb.2013.05.011
Please cite this article in press as: A. Gupta, et al., Current status on development of steroids as anticancer agents, J. Steroid Biochem. Mol. Biol.
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O
[17β -hydroxylase/17, 20-lyase] HO HO 3 steps Progesterone Cholesterol C-21 Steroid C-27 Steroid
O
HO Dehydroepiandrosterone C-19 Steroid [3β -Hydroxysteroid dehydrogenase]
O
HO 4-Androstrosten-3,17-dione C-19 Steroid
[Aromatase]
O O OH
[17β -Hydroxysteroid dehydrogenase] [Steroidsulfatase] O HO S O HO HO
O
Estrone sulphate Estrone Estradiol
C-18 Steroid, Potent C-18 Steroid, inactive C-18 Steroid
form of estrogen endogenous estrogen
Fig. 1. Schematic presentation of steroidogenesis.
58 and endometrial cancers. Despite several advances made towards secondary sexual characteristics in females in particular. Steroid 85
59 the diagnosis, prevention and cure of cancer, it remains one of the hormone related carcinogenesis is mainly due to accelerated cell 86
60 major causes of human morbidity and mortality. Presently, it is proliferation. These metabolizing enzymes and steroidal recep- 87
61 second largest killer to human being after cardiovascular disease tors are major players. Estrogens also play a crucial role in the 88
62 which accounted 7.6 million deaths in 2008 (13% of total human cell proliferation. However, over-expression of estrogens stimulate 89
63 deaths) and projected to continue rising 13.1 million by 2030 [2]. excess proliferation of hormone sensitive cells leading to various 90
64 Therefore, it is a need to have safer and more effective anticancer types of hormone dependent cancer such as breast, uterine, ovar- 91
65 drug and indeed a challenge for medicinal chemists. ian, prostate and endometrial cancers [4]. Some of the cancers are 92
66 Steroidogenesis and its effect on human physiology has been due to rise in reductive activity and decrease in oxidative activity 93
67 most fascinating aspect to Biochemists and Endocrinologists. Var- towards the estrogens and androgens. Nevertheless, steroids have 94
68 ious types of steroid molecules are synthesized biochemically been centre of research for the development of antihormonal drugs. 95
69 in human body involving conversion of cholesterol (C27) into There are various approaches to reduce the hormonal response 96
70 progestins (C21) followed by androgens (C19) and finally into of cancer cells. Either biosynthetic enzyme inhibitors are used to 97
71 estrogens (C18) with the help of various enzymes (Fig. 1). This mul- reduce the biosynthesis of endogenous hormone or a better lig- 98
72 tistep process is known as steroidogenesis [3]. As described above and to replace endogenous steroid hormone from binding with 99
73 cholesterol is the main source of steroids in ovaries. Enzymes such specific receptor. Sulfatase inhibitors and aromatase inhibitors are 100
74 as aromatase (CYP450arom), 17-hydroxysteroid dehydrogenase enzyme inhibitors while, antiestrogens are competitive inhibitors 101
75 (17-HSDs) are essentially required in the last step of estrogen of estrogens. Antiprogestins have also been reported to act as 102
76 biosynthesis while steroid sulfatase (STS) is required for intercon- antiproliferative agents. A brief account of steroidal anticancer 103
77 version from inactive form of estrogen to their active form. Various agents has been shown in Fig. 2. 104
78 important steroid hormones are synthesized by this process such In the drug discovery, steroids have been a prime focus of 105
79 as progestins, androgens, estrogens, glucocorticoids and mineralo- research not only due to their fascinating structural framework [5], 106
80 corticoids. but also due to their astonishing array of pharmacological proper- 107
81 Among these hormones, biosynthesized from cholesterol, estro- ties. Steroids have an excellent ability to penetrate cell membranes 108
82 gens are the main hormone responsible for the maintenance of and bind to the nuclear and membrane receptors. Even a small 109
83 Central Nervous System (CNS), Cardiovascular system (CVS) and change in steroid moiety can elicit an extensive biological response. 110
84 bones in both males and females in general and development of All these facts have attracted Medicinal Chemists and Biochemists 111
Please cite this article in press as: A. Gupta, et al., Current status on development of steroids as anticancer agents, J. Steroid Biochem. Mol. Biol.
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Steroids as anticancer agents
Antihormonal/antiproliferative Cytotoxic (through non-hormonal targets)
Biosynthesis inhibitors Action inhibitors Semisynthetic (through enzyme inhibition) (through Receptors) Naturally occurring
Antiestrogens Antiprogestins
Steroid sulfatase Aromatase Hydroxysteroid dehydrogenase
inhibitors (STSI) inhibitors (AI) inhibitors (17 HSDI)
Fig. 2. Classification of steroidal anticancer agents.
112 to explore these after modifying them suitably to induce various 2. Steroids as antiproliferative agents 120
113 pharmacological properties. Different type of steroids have been
114 modified as cytotoxic and cytostatic (antiproliferative) anticancer 2.1. Enzyme inhibitors 121
115 agents. The present review is a concise report on steroid based
116 anticancer molecules for the treatment of various types of can- 2.1.1. Steroid sulfatase inhibitors 122
117 cer. Most of the steroidal anticancer drugs have been developed Steroids sulfatase (EC 3.1.6.2) is a member of mammalian sul- 123
118 as enzyme inhibitors and cytotoxic drugs. This brief update covers fatase superfamily catalyzing hydrolysis of sulfate ester bonds of 124
119 the potential leads developed during past 25 years. steroid sulfates to free hydroxysteroids. There are several well 125
Table 1
Some potential steroidal STS inhibitors.
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Table 1 (Continued)
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Table 2
Some of the potential aromatase inhibitors.
126 known endogenous substrates of steroid sulfatase (STS) like estrone carcinoma [14] as well. In colon carcinoma the tissue concentration 153
127 sulfate (E1S), cholesterol sulfate (CHOLS), dehydroepiandrosterone of estrogens was found to be higher, but it could not be properly 154
128 sulfate (DHEAS) and pregnenolone sulfate (PREGS) [6]. The tissue correlated to STS activity. Overall, estrogen level is high in all these 155
129 distribution of STS varies considerably among the different mam- type of cancers [15]. Since, higher level of estrogens produced by 156
130 mals. In humans, STS enzyme is actively present in placenta, adrenal STS pathway contributes to the progression of several endocrine 157
131 glands, ovary, prostate, testis, skin and brain. STS converts estrone related carcinomas, STS inhibitors may be clinically effective to stop 158
132 sulfate (inactive form of estrogen) to estrone (active form). This further proliferation by curtailing STS enzyme activity. 159
133 conversion is a reversible reaction where STS catalyses forward The basic structural requirement for this class of inhibitors is a 160
134 reaction and reversible reaction is catalyzed by another enzyme sulfamate ester that should be linked to an aryl group. The position 161
135 known as steroid sulfotransferase [7]. In normal condition both should be preferably at 3-position of steroidal skeleton. Various STS 162
136 reactions are in equilibrium. inhibitors have been reported in literature incorporating steroidal 163
137 The steroid sulfatase plays a crucial role in the regulation of nucleus which have been summarized in Table 1 [16–29]. These 164
138 tissue concentration of estrogens and androgens in human tar- have been categorized as first and second generation STS inhibitors 165
139 get organs. Over-expression of STS activity in the tissues leads depending on their biological activities. The first generation STS 166
140 to high estrogenic response which is considered as the prognosis inhibitors are purely hormone inhibitors, while second generation 167
141 of various cancers like prostate, breast, etc. Estrone sulfatase has STS inhibitors are dual action inhibitors (hormone as well as tubu- 168
142 longer half life than the other estrogens [8]. It is 5–10 times higher lin polymerization inhibitors). The first generation STS inhibitors 169
143 than unconjugated estrogens, i.e. estrone, estradiol and estriol dur- are antiproliferative (cytostatic) and latter are cytotoxic as well. 170
144 ing menstrual cycle and postmenopausal women [9,10]. Pasquilini The second generation STS inhibitors are mainly synthesized as 171
145 et al. (2004) found higher tissue concentration of estradiol in breast 2-methoxyestradiol (2ME2) analogues. These compounds also pos- 172
146 carcinoma [10]. It was 5-fold higher in premenopausal women and sess antiangiogenic property. Now, a third generation STS inhibitors 173
147 23-fold higher in post-menopausal women. STS enzyme activity are underway where compounds are able to inhibit both STS and 174
148 was detected in majority of breast carcinomas [11]. STS mRNA aromatase enzymes. But, so far no effective lead could be developed 175
149 expression was higher in breast carcinoma tissues and has been on steroidal framework as third generation STS inhibitor. Several 176
150 significantly associated with the progression of the disease [12]. research groups such as M.J. Reed, A. Purohit, D. Poirier, T. Suzuki, 177
151 Similarly, STS enzymatic activity was found significantly higher in S. Ahmed and S.P. Newman have enormously contributed in this 178
152 endometrial carcinoma [13], ovarian carcinoma [14] and prostate area. Some of the notable leads have been described. 179
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Table 2 (Continued)
180 2.1.2. Aromatase inhibitors estrogen. Aromatase enzyme is considered as one of the most 190
181 In the last step of biosynthesis, aromatase enzyme which is important CYP because of its role in the development of female 191
182 a member of cytochrome P450 (CYP19A1) converts androgens characteristics. However, it is over-expressed in breast cancer 192
183 (C19) to estrogens (estrone and estradiol, C18). This important tissues and considered as a target for the development of anti- 193
184 irreversible step occurs in ovary. Aromatase is found in ovary, pla- breast cancer agents [30]. An aromatase inhibitor (AI) efficiently 194
185 centa, bone, skin, testis, brain and adipose tissues. At menopause checks aromatase enzyme action which reduces biosynthesis of 195
186 and post-menopause conditions, when ovaries are non-functional estrogens and ultimately proliferation of cancer cells. AIs are cat- 196
187 the peripheral conversion of androgens provide estrogens by egorized in two subclasses namely Type I and II. Generally, type 197
188 aromatase enzyme. Androstenedione is converted to estrone, I AIs are steroidal in nature and act irreversibly, while type II 198
189 while testosterone is converted to estradiol (E2), the most potent inhibitors are non-steroidal acting reversibly. Steroidal AIs are also 199
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Table 3
Some of important 17-hydroxysteroid dehydrogenase inhibitors.
200 known as ‘suicidal inhibitors’. In case of steroidal AIs, generally of breast cancer. Aromatase inhibitors are very effective for the 211
201 androstene-3,17-dione nucleus has been considered very impor- treatment of estrogen dependent cancers. However, associated side 212
202 tant to interact with aromatase enzyme. There are several closely effects like hot flashes, vaginal dryness and headache are very 213
203 packed hydrophobic residues in the active site of aromatase, which common with use of AIs. It is also reported that induction of osteo- 214
204 provide stack against ␣-face backbone of adrostenedione [31,32]. porosis and endometrial carcinoma are possible in some cases [31]. 215
205 Steroidal inhibitors bind covalently to the aromatase and convert it AIs are very effective in cancer treatment, but drug resistance prob- 216
206 to a reactive intermediate causing irreversible inactivation [33]. On lem is often encountered. Researchers are making their efforts to 217
207 the other hand, type II AIs bind non-covalently to the heme of the have a safer aromatase inhibitor devoid of these side effects. In 218
208 aromatase enzyme and prevent binding of endogenous androgens the past few years scientists across the globe have reported many 219
209 to it [31]. Presently, exemestane (37), a type I AI, anastrozole and new therapeutics of this class with improved biological profile. The 220
210 letrozole, type II AIs, are approved by US FDA for the treatment research groups of A. Brodie, M. Akhtar, S. Chen, A.M. Brodie, D. 221
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Table 3 (Continued)
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Table 3 (Continued)
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Table 4
Some important steroidal antiestrogens.
Entry Compound name Structure Activity Ref.
1. SR16137 (153) Selective estrogen receptor modulator, [75]
antiestrogenic to breast tissues. It has
beneficial effects to bones
2. SR16234 (154) Orally active antiestrogen, under [76]
clinical trial
3. RU3941 (155) Antiproliferative against MCF-7 [76]
carcinoma cells, pure antiestrogen, no
utereotropic activity
4. RU51625 (156) Better antiproliferative than tamoxifen [76]
against MCF-7 cells. No uterotropic
activity
5. ICI 164,384 (157) More inhibitory than tamoxifen [75]
against MCF-7 and ZR-75-1 breast
cancer cells and DMBA induced
mammary tumour. Orally active
6. 11-Perfluorenated Strong antiproliferative activity against [77]
fulvestrant (158) MCF-7 cells. No down-regulation of
ER␣
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Table 4 (Continued)
Entry Compound name Structure Activity Ref.
7. 11- better antiproliferative than [78]
Amidoalkoxyphenyl 4-hydroxytamoxifen against MCF-7
estradiol (159)
8. 11-(4- Strong antiproliferative against MCF-7 [75]
Pentafluorinated and T47D. Effective in in vivo
alkylsulphonylpentay- mammary carcinoma in nude mice
loxyphenyl estradiol model
(160)
␣
9. Fulvestrant (161) Selective ER down-regulator, no [79]
agonistic effect, drug for metastatic
breast cancer. IC50 (MCF-7) = 0.29 nM
Table 5
Some potential cytotoxic steroids from natural origin.
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Table 5 (Continued)
222 Ghosh, R.C. Coombes and M. Numazawa, etc. have contributed sig- DHEA, one of the key intermediates in steroidogenesis is con- 245
5
223 nificantly in this area. A brief description of some of the emerged verted to -androstene-3,17-diol by 17-HSD1 and 17-HSD5 246
224 AIs is presented in Table 2 [34–47]. [50]. This reversible reaction is driven by 17-HSD2 and 17-HSD4 247
to backward direction [51]. Testosterone oxidation is catalyzed 248
ˇ   ␣
225 2.1.3. 17 -Hydroxysteroid dehydrogenase inhibitors by 17 -HSD2 and 17 -HSD8 [52]. 5 -Dihydrotestosterone is 249
␣   
226 Enzyme group affecting availability of biologically active converted to 5 -androstane-3 ,17 -diol by 17 -HSD7 [53] and 250
  
227 estrogens and androgens is the family of 17-hydroxysteroid reversed by 17 -HSD2, 17 -HSD5 and 17 -HSD11. 251
4
228 dehydrogenase (17-HSD). 17-HSD [EC 1.1.1.51] is an alcohol -Androstenedione and testosterone are converted to estrone 252
229 oxidoreductase enzyme which catalyses dehydrogenation of 17- and estradiol by aromatase enzyme. Estrone is oxidized to biolog- 253
  
230 hydroxysteroids. In steroidogenesis, various interconversions of ically potent estradiol by 17 -HSD1, 17 -HSD5 and 17 -HSD7. 254
 
231 steroidal substrate from their inactive to active from or vice Inactivation of estradiol is done by 17 -HSD2 and 17 -HSD8 255
 
232 versa, e.g. dehydroepiandrosterone (DHEA) to androstenediol, in breast and uterus epithelium and also by 17 -HSD4, 17 - 256
233 androstenedione to testosterone, and estrone to estradiol respec- HSD10 in human peripheral tissues [52]. Considering pivotal role 257

234 tively are catalyzed by this enzyme. There are several other of 17 -HSDs in steroid hormone modulation and their substrate 258
235 hydroxysteroids dehydrogenases also, converting steroids at posi- specificity, these are promising targets for various types of dis- 259
236 tions 3, 5, 11 and 20 of steroidal framework. Among these 17-HSD eases [48] like breast cancer [54], endometriosis, osteoporosis and 260
237 is the most important, modulating biological potency of both prostate cancer [55]. 261
 
238 estrogens and androgens by redox reaction at 17-position. So far The 17 -hydroxysteroid dehydrogenase (17 -HSD) enzyme 262
239 fourteen different forms of this enzyme have been discovered family is involved in the biosynthesis of active steroids and its inhi- 263
240 denoted as 17-HSD1 to 17-HSD14 [48]. 17-HSDs with mainly bition constitutes an interesting approach for treating estrogen- 264

241 oxidative activities tend to decrease the potency of estrogens and and androgen-dependent cancers. 17 -HSD1 is expressed in prolif- 265
242 androgens which ultimately may protect tissues from excessive eration of human breast carcinomas [56]. Further, its co-expression 266
243 hormone action. Their expression is in a wide variety of tissues was positively correlated with estrogen receptor status in inva- 267
244 such as breast, ovary, uterus, liver, prostate and kidney [49]. sive ductal carcinoma. It is indicated that breast carcinoma can 268
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Table 5 (Continued)
269 effectively convert estrone to estradiol to exert higher levels of activity. Recently, other positions such as 15, 16 and 17 of steroidal 286
270 estrogenicity in tumour cells [57]. Estradiol has been shown to nucleus in particular estrone and estradiol, have also been modified 287
271 accumulate in the malignant breast tissues. In prostate cancer cells with a view to get a potential antiestrogenic molecule. However, 288
272 multiple forms of 17-HSDs have been over-expressed, whereas, with only few exceptions such as steroidal antiestrogen namely SR 289
273 17-HSD2 expression is significantly decreased in colon carcinoma 16137 (153) and SR 16234 (154), modifications at 15, 16 and 17 of 290
274 [57]. steroidal nucleus lead to development of mainly enzyme inhibitors, 291
275 Some of the major contributors of the area include Jerzy cytotoxic molecules or dual acting antiestrogens. The potential 292
276 Adamski, R.W. Hartmann, F. Labrie, D. Poirier, P. Vihko, R. Mind- steroidal antiestrogens were achieved through modification of 293
277 nich, T.M. Penning, etc. A brief description of some of the notable 7␣ or 11-position of the estradiol which led to the discovery of 294
278 leads is given in Table 3 [58–74]. RU 3941 (155), RU 51625 (156), ICI-164384 (157) and fulvestrant 295
(161), etc. Complete structure activity relationship of these com- 296
297
279 2.2. Antiestrogens pounds reveals that length of spacer chain between steroidal core
and functional group plays crucial role in biological response. A 298
␣ 299
280 Antiestrogens compete with endogenous estrogens for estrogen limited C4–C6 carbon chain is required at 7 -position for pure
300
281 receptor (ER) binding and also for direct interaction with growth antiestrogenic property. Increasing the carbon chain-length does
301
282 factors which ultimately lead to inhibition of estrogenic action. not help in activity enhancement. Introduction of an aryl group at
␣
 302
283 From receptor ligand topology and X-ray studies of ligand binding 7 -position increases agonistic property. While at 11 -position,
303
284 pocket of ER, it has been learnt that any modification at position an aryl group is preferably required for antiestrogenic activity
␣ 304
285 7 or 11 is well tolerated and leads to induction of antiestrogenic [75]. Research groups of J.A. Katzenellenbogen, R.N. Hansen, S.
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Table 5 (Continued)
305 Ray, R.W. Hartman, Y.J. Abdul-Hajj, J.M. Renoir, J.A. Gustafsson, antiprogestins was induced through inhibition of cyclin depen- 323
306 R.W. Brueggemeier, etc. have contributed in this area significantly. dent kinase-2 (CDK-2) [84]. CDK-2 has been shown to be critical 324
307 Some potential steroidal antiestrogens and their biological activity in promoting the transition of cells in the cell cycle from G1 to S 325
308 profile have been collated in Table 4. phase. However, all these effects were not dependent upon expres- 326
sion of classical nuclear progesterone receptor. Lonaprisan (165, 327
ZK230211) another antiprogestin is under phase II clinical trial for 328
309 2.3. Antiprogestins
postmenopausal women with metastatic breast cancer [85] (Fig. 3). Q2 329
310 Antiprogestins are mainly utilized in reproductive medicines
311 and less explored as anticancer agents. However, mifepristone 3. Steroids as cytotoxic agents 330
312 (162, RU-38486) an early abortifacient has been extensively
313 explored as cytostatic agent. In various in vitro studies mifepri- Selection of cancer chemotherapeutics for the treatment of 331
314 stone has inhibited growth of neuroblatoma, breast (MCF-7 and disease is mainly based on the stage of cancer. At initial stage, 332
315 T-47D) and ovarian cancers cell lines. ORG-31710 (163) and CDB- when cancer formation begins, use of cytostatic (antiproliferative 333
316 2914 (164, ulipristal acetate) are other antiprogestins of similar or enzyme inhibitor) drug is a preferred choice while at advance 334
␣
317 structure differing in 17 -side chain, exhibiting similar effects. stage of disease various cytotoxic drugs having different modes 335
318 ORG-31710 effectively increased apoptosis in human pre-ovulatory of action are preferred. In case of drug resistance, combination 336
319 granulose cells [80] while, 164 inhibited proliferation of uter- of either antiestrogen with enzyme inhibitor or cytotoxic drug 337
320 ine leiomyoma cells by inducing apoptosis [81]. Both 167 and with enzyme inhibitor is given to overcome the problem. Diver- 338
321 168 reduced the growth of DMBA induced breast tumours in rats sified classes of compounds have been developed as cytotoxic 339
322 [82,83]. This antiproliferative effect of all the three (162–164) drugs such as paclitaxel, combretastatin, doxorubicin, cisplatin and 340
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N N OH O CH3 N O O OAc OH CF2-CF3
O O O 162 CH3 163 164 O
165
Fig. 3. Some of the antiprogestins as antiproliferative agents.
341 fluorouracil. Various cytotoxic steroidal molecules active against A brief coverage of some steroid based important drugs as well 348
342 different human cancer cell lines have either been isolated from possible leads is presented in Table 4. A proper structure activ- 349
343 natural sources or rationally synthesized. These molecules gener- ity relationship has also been established in most of the cases 350
344 ally follow different modes of action through non-hormonal targets particularly in case of molecules having potential for future drug 351
345 like tubulin, topoisomerase, etc. Beside their anticancer activity, development. 352
346 these molecules may or may not have antihormonal effects. Such Despite the use of steroids for the development of antiprolif- 353
347 molecules have been classified in this study as cytotoxic steroids. erative, cytotoxic compounds and enzyme inhibitors, these have 354
Table 6
Synthetically modified steroids.
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Table 6 (Continued)
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Table 6 (Continued)
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Table 6 (Continued)
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Table 6 (Continued)
Please cite this article in press as: A. Gupta, et al., Current status on development of steroids as anticancer agents, J. Steroid Biochem. Mol. Biol.
(2013), http://dx.doi.org/10.1016/j.jsbmb.2013.05.011
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20 A. Gupta et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2013) xxx–xxx
Table 6 (Continued)
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(2013), http://dx.doi.org/10.1016/j.jsbmb.2013.05.011
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Table 6 (Continued)
Please cite this article in press as: A. Gupta, et al., Current status on development of steroids as anticancer agents, J. Steroid Biochem. Mol. Biol.
(2013), http://dx.doi.org/10.1016/j.jsbmb.2013.05.011
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22 A. Gupta et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2013) xxx–xxx
Table 6 (Continued)
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(2013), http://dx.doi.org/10.1016/j.jsbmb.2013.05.011
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Table 6 (Continued)
Please cite this article in press as: A. Gupta, et al., Current status on development of steroids as anticancer agents, J. Steroid Biochem. Mol. Biol.
(2013), http://dx.doi.org/10.1016/j.jsbmb.2013.05.011
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Table 6 (Continued)
355 also been successfully used as a mean of drug delivery in the hormone, so that the drug can bind to the receptor. These molecules 374
356 form of a carrier molecule. Based on this concept several steroid have good bioavailability and can cross lipophilic membranes. Both 375
357 conjugates have been synthesized after linking steroidal compo- steroidal and non-steroidal pharmacophores have been tried to get 376
358 nent with cytotoxic molecule such as nucleosides, organometallics, an ideal drug. 377
359 nitrogen mustards and doxorubicin. These conjugates provide site STS, an attractive target to develop antihormonal therapy is 378
360 specific delivery of cytotoxic component to achieve selectivity. comparatively a newer approach. So far no drug could be developed 379
361 Such molecules elicit their anticancer potential at the site of action based on this approach, but a few are under clinical trials. Irosu- 380
362 because of their cytotoxic part following their specific mode of stat (667Coumate) a non-steroidal first generation STS inhibitor 381
363 action. Some metal complexes have also been synthesized with is under phase II clinical trial and 2ME2bisMATE (9, STX140), a 382
364 platinum and ruthenium metals. Platinum complexes crosslink steroidal second generation STS inhibitor is under phase I clin- 383
365 DNA and interfere cell division by mitosis. Thus, ultimately induce ical trial. Both the investigational drugs are expected to treat 384
366 apoptosis. Diversified derivatives have been achieved on modifica- endocrine resistant breast carcinomas. The 2-methoxyestradiol 385
367 tion of steroids. Structurally rings A and D of steroids were more based STS inhibitors such as 2-methoxy/2-ethoxy estradiol sulfa- 386
368 prone for modifications. Hence, most of the analogues have been mates (10–17 and 22–33) seem to be potential candidates 387
369 developed after modification of these rings. A concise description [23,26,27]. These dual action antiproliferative agents are less likely 388
370 of lead molecules has been provided in Tables 5 and 6 [86–165]. to develop drug resistance. 389
Aromatase inhibitors block the last step of steroidogenesis and 390
371 4. Conclusions may not affect the normal synthesis of other endogenous steroids 391
such as androgens and progesterones. Exemestane (37), an orally 392
372 There are several advantages associated to take steroidal phar- active steroidal AI, is in clinical use and is given after tamox- 393
373 macophores. Structural similarity is required with the endogenous ifen treatment. AIs have been very effective in clinical use, but 394
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395 these are associated with side effects like risk of osteoporosis, joint Steroidal conjugates (405–444) have been prepared with vari- 461
396 disorders (arthritis). Statins and bisphosphonates are given along ous cytotoxic drugs such as nucleosides, paclitaxel, chlorambucil 462
397 with during the treatment to overcome these problems. Among and metal complexes. Estradiol conjugates prepared by modi- 463
398 the various emerging leads, 6-alkynyloxyandrost, 1,4-dien, 17-one fication at rings A (416–437 and 435–438) and D (439–442) 464
399 series (65–68) seems to possess impressive AIs and antiprolifera- showed potential anticancer activity in both ER+ and ER− cell lines 465
400 tive activities [46]. [161,134,163]. However, A ring conjugates were non-selective to ER 466
401 17-HSDs type 1, 2 and 3 play a crucial role in androgen and while D rings conjugates had some selectivity. Recently, Dao and 467
402 estrogen biosynthesis and are suitable targets to modulate the con- Hanson reported that bioconjugates of E2 were not of much suc- 468
403 centration of the estradiol (E2) and testosterone in case of steroid cess as researchers were unable to introduce linking groups onto 469
404 dependent cancers. As they act selectivity in an intracrine manner, the E2 scaffold without seriously compromising binding affinity 470
405 inhibitors of these enzymes might be superior to endocrine ther- [166]. A recent report on platinum complexes by Prof. G. Berube 471
406 apies like aromatase inhibitors, antiestrogens and SERMs due to group exhibits ER␣ selectivity in some D ring modified E2 conju- 472
407 off-target effects. gates. Considering the associated side effects with cytotoxic drugs, 473
408 Fulvestrant (161), an antiestrogen, is in clinical use for tamox- the approach of delivering them selectively to the site of action by 474
409 ifen resistant breast cancer treatment and second line metastatic the use of steroids is appreciable and needs further exploration. 475
410 anti-breast cancer drug. It is marketed by Astra Geneca under the In a nutshell, steroid based anticancer drugs have bright 476
411 trade name of ‘Faslodex’. It is reported that fulvestrant is the only prospects with a limitation of inherent hormonal effects. A bet- 477
412 steroidal antiestrogen that down-regulates estrogen receptor (ER) ter understanding about structure–receptor properties and careful 478
413 and is devoid of any estrogenic activity. However, compounds such modifications by the researchers may deliver successful drug in 479
414 as steroidal antiestrogen namely SR 16137 (153) and SR 16234 future. 480
415 (154) follow ER mediated mode of action as followed by other clas-
416 sical antiestrogens such as tamoxifen and raloxifene. Use of enzyme
Conflict of interest 481
417 inhibitors such as aromatase, sulfatase and 17-hydroxysteroid
418 dehydrogenase inhibitors in cancer chemotherapy is effective and
There is no conflict of interest. 482
419 preferred at very initial stage of cancer. However, their use brings
420 near about complete inhibition of estrogen biosynthesis which is
Acknowledgement 483
421 undesirable since estrogens are required for proper maintenance
422 of body. Antihormonal therapy has been a moderate approach to
The constant encouragement and support received from Direc- 484
423 stop the further proliferation of cancer cells at early stage of can-
tor CSIR-CIMAP is duly acknowledged. 485
424 cer. In case of drug resistance for a particular drug, most of the
425 time these antihormonal agents are used with enzyme inhibitors
426
in adjuvant therapy such as use of tamoxifen and letrozole. Because References Q3 486
427 of a vast scope for modification in the existing leads and synthe-
[1] P. Irigaray, D. Belpomme, Basic properties and molecular mechanisms of 487
428 sis of stereochemically diversified molecules as estrogen receptor
exogenous chemical carcinogens, Carcinogenesis 31 (2010) 135–148. 488
429 modulators, much attention has been given on the development
[2] WHO Cancer: Factsheet No. 297, February 2012. 489
430
of non-steroidal antihormonal agents. However, steroidal antie- [3] W.L. Miller, R.J. Auchus, The molecular biology, biochemistry and physiology 490
431 strogens have not been focused extensively. Therefore, as far as of human steroidogenesis and its disorders, Endocrine Reviews 32 (2011) 491
81–151. 492
432 chemotherapy of hormone dependent cancers is concern, there
[4] G.G. Chen, Q. Zeng, G.M. Tse, Estrogen and its receptors in cancer, Medicinal 493
433 is requirement for exploration of novel steroidal antiestrogenic
Research Reviews 28 (2008) 954–974. 494
434 as well as some dual acting molecules having different modes of [5] M.S. Brown, J.L. Goldstein, A receptor-mediated pathway for choles- 495
terol homeostasis, in: Nobel lecture, Physiology or Medicine, Stockholm, 496
435 action. Other novel strategies to selectively target or stimulate ER␣
December, 1985, pp. 284–324. 497
436 or ER may appear to be more effective approach to tackle such
[6] M.J. Reed, A. Purohit, L.W.L. Woo, S.P. Newman, B.V.L. Potter, Steroid sulfa- 498
437 hormone dependent cancers. Receptor subtype selective ligands tase: molecular biology, regulation, and inhibition, Endocrinology Reviews 499
26 (2005) 171–202. 500
438 may help in the reduction of cancers and same time will not curtail
[7] R. Hobkrik, Steroid sulfation: current concepts, Trends in Endocrinology 501
439 beneficial effects of estrogens.
Metabolism 4 (1993) 69–74. 502
440 Cytotoxic steroids are not necessarily selective anticancer [8] H.J. Ruder, D.L. Loriaux, M.B. Lipsett, Estrone sulfate: production rate and 503
metabolism in man, Journal of Clinical Investigation 51 (1972) 1020–1023. 504
441 agents. But, these compounds have ability to kill the existing
[9] C.T. Noel, M.J. Reed, H.S. Jacobs, V.H.T. James, The plasma concentration of 505
442 tumour. Most of the derivatisations have been made after modi-
oestrone sulphate in post-menopausal women: lack of diurnal variation, 506
443
fication in A, B and D rings of steroids. Some of such derivatives effect of ovariectomy, age and weight, Journal of Steroid Biochemistry and 507
Molecular Biology 14 (1981) 1101–1105. 508
444 exhibited cytotoxicity by tubulin polymerization inhibition or
[10] J.R. Pasqualini, The selective estrogen enzyme modulators in breast cancer: a 509
445 topoisomerase inhibition. Among the naturally occurring steroids
review, Biochimica et Biophysica Acta 1654 (2004) 123–143. 510
446
hydroxyperoxide desmosterols (185–190) isolated from Galaxaura [11] T.R. Evans, M.G. Rowlands, M. Law, R.C. Coombes, Intratumoral oestrone sul- 511
447 marginata, Ghalakinosides (191–198) from Pergularia tomentosa, phatase activity as a prognostic marker in human breast carcinoma, British 512
Journal of Cancer 69 (1994) 555–561. 513
448 19-hydroxy, 2-oxovoruscharin (210) and hellebrin D (211) from
[12] T. Utsumi, N. Yoshimura, S. Takenchi, M. Maruta, K. Maeda, N. Harada, Elevated 514
449 Calotropis procera exhibiting high anticancer potential should fur-
steroid sulphatase expression in breast cancer, Journal of Steroid Biochem- 515
450 ther be explored for mode of action and toxicity studies, carefully istry and Molecular Biology 73 (2000) 141–145. 516
[13] O. Abulafia, Y.C. Lee, A. Wagreich, K. Economos, E. Serur, V.L. Nacharaju, 517
451 [95,96,101,102].
Sulfatase activity in normal and neoplastic endometrium, Gynecologic and 518
452 Among the modified estradiols, 2-methoxyestradiol analogues
Obstetric Investigation 67 (2009) 57–60. 519
453 (230–232 and 234–237) have exhibited very potent anticancer [14] J.M. Day, A. Purohit, H.J. Tutill, P.A. Foster, L.W. Woo, B.V. Potter, M.J. Reed, The 520
development of steroid sulfatase inhibitors for hormone-dependent cancer 521
454 activity [108,110]. All these leads are potent inhibitors of micro-
therapy, Annals of New York Academy of Sciences 1155 (2009) 80–87. 522
455 tubulin polymerase. A few of them are already under clinical trials.
[15] T. Suzuki, Y. Miki, Y. Nakamura, K. Ito, H. Sasano, Steroid sulfatase and estrogen 523
456 Among the androstane derivatives most of the modifications have sulfotransferase in human carcinomas, Molecular and Cellular Endocrinology 524
340 (2011) 148–153. 525
457 been done at C16 and C17 positions. Various compounds with
[16] A. Billich, P. Nussbaumer, P. Lehr, Stimulation of MCF-7 breast cancer cell 526
458 nitrogen heterocycles (308–314 and 370–371) were potential cyto-
proliferation by estrone sulfate and dehydroepiandrosterone sulfate: inhi- 527
459
toxic molecules. 3-Azido withaferin A (339) had impressive activity bition by novel non-steroidal steroid sulfatase inhibitors, Journal of Steroid 528
460 [132,137,146]. Biochemistry and Molecular Biology 73 (2000) 225–235. 529
Please cite this article in press as: A. Gupta, et al., Current status on development of steroids as anticancer agents, J. Steroid Biochem. Mol. Biol.
(2013), http://dx.doi.org/10.1016/j.jsbmb.2013.05.011
G Model
SBMB 3991 1–29 ARTICLE IN PRESS
26 A. Gupta et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2013) xxx–xxx
530 [17] G. Chetrite, J. Paris, J. Botella, J.R. Pasqualini, Effect of nomegestrol acetate [42] M.R. Yadav, P.M. Sabale, R. Giridhar, C. Zimmer, R.W. Hartmann, Steroidal 616
531 on estrone-sulfatase and 17-hydroxysteroid dehydrogenase activities in carbonitriles as potential aromatase inhibitors, Steroids 77 (2012) 850–857. 617
532 human breast cancer cells, Journal of Steroid Biochemistry and Molecular [43] M. Nagaoka, Y. Watari, H. Yajima, K. Tsukioka, Y. Muroi, K. Yamada, M. 618
533 Biology 58 (1996) 525–531. Numazawa, Structure–activity relationships of 3-deoxy androgens as aro- 619
534 [18] H. Ishida, T. Nakata, M. Suzuki, Y. Shiotsu, H. Tanaka, N. Sato, et al., A novel matase inhibitors. Synthesis and biochemical studies of 4-substituted 4-ene 620
535 steroidal selective steroid sulfatase inhibitor KW-2581 inhibits sulfated estro- and 5-ene steroids, Steroids 68 (2003) 533–542. 621
536 gen dependent growth of breast cancer cells in-vitro and in animal models, [44] M.A.C. Neves, T.C.P. Dinis, G. Colombo, M.L. SaeMelo, An efficient steroid 622
537 Breast Cancer Research and Treatment 106 (2007) 215–217. pharmacophore-based strategy to identify new aromatase inhibitors, Euro- 623
538 [19] (a) Y. Jinbo, Y. Inoue, Novel estradiol derivatives, PCT Int. Appl. WO pean Journal of Medical Chemistry 44 (2009) 4121–4127. 624
539 2000053620 (2000); [45] M. Numazawa, W. Handa, C. Hasegawa, M. Takahashi, Structure–activity rela- 625
540 (b) L.C. Ciobanu, R.P. Boivin, V. Luu, F. Labrie, D. Poirier, Potent inhibition tionships of 2␣-substituted androstenedione analogs as aromatase inhibitors 626
541 of steroid sulfatase activity by 3-O-sulfamate 17␣-benzyl(or 4 -tert- and their aromatization reactions, Journal of Steroid Biochemistry and Molec- 627
542 butylbenzyl)estra-1,3,5(10)-trienes: combination of two substituents at ular Biology 97 (2005) 353–359. 628
␣
543 positions C3 and C17 of estradiol, Journal of Medicinal Chemistry 42 (1999) [46] D. Ghosh, J. Lo, D. Morton, D. Valette, J. Xi, J. Griswold, S. Hubbell, C. Egbuta, 629
544 2280–2286. W. Jiang, J. An, H.M.L. Davies, Novel aromatase inhibitors by structure-guided 630
545 [20] R.H. Peters, W.R. Chao, B. Sato, K. Shigeno, N.T. Zaveri, M. Tanabe, Steroidal design, Journal of Medicinal Chemistry 55 (2012) 8464–8476. 631
546 oxathiazine inhibitors of estrone sulfatase, Steroids 68 (2003) 97–110. [47] C. Varela, E.J.T. da Silva, C. Amaral, G.C. da Silva, T. Baptista, S. Alcaro, G. Costa, 632
547 [21] M.L. MacCarthy, P.A. Townsend, A. Purohit, Differential effects of estrone and R.A. Carvalho, N.A.A. Teixeira, F.M.F. Roleira, New structure–activity rela- 633
548 estrone-3-O-sulfamate derivatives on mitotic arrest, apoptosis, and micro- tionships of A- and D-ring modified steroidal aromatase inhibitors: design, 634
549 tubule assembly in human breast cancer cells, Cancer Research 60 (2001) synthesis, and biochemical evaluation, Journal of Medicinal Chemistry 55 635
550 5441–5450. (2012) 3992–4002. 636
551 [22] M. Wang, L. Xu, M. gao, K.D. Miller, G.W. Sledge, Q.H. Zheng, Synthesis of [48] M. Oberwinkler, C. Henn, G. Moller, T. Klein, M. Negri, A. Oster, A. Spadaro, 637

552 2-[11C]methoxy-3,17 -OO-bis(sulfamoyl)estradiol as a new potential PET R. Werth, M. Wetzel, K. Xu, M. Frotscher, R.W. Hartmann, J. Adamski, 17- 638
553 agent for imaging of steroid sulfatase (STS) in cancers, Steroids 77 (2012) Hydroxysteroid dehydrogenases (17-HSDs) as therapeutic targets: protein 639
554 864–870. structures, functions, and recent progress in inhibitor development, Journal 640
555 [23] F. Jourdan, M.P. Leese, W. Dohle, E. Ferrandis, S.P. Newman, S. Chander, A. of Steroid Biochemistry and Molecular Biology 125 (2011) 66–82. 641
556 Purohit, B.V.L. Potter, Structure–activity relationships of C-17-substituted [49] P. Vihko, P. Harkonen, O. Oduwole, S. Torn, R. Kurkela, K. Porvari, A. Pulkka, V. 642
557 estratriene-3-O-sulfamates as anticancer agents, Journal of Medicinal Chem- Isomaa, 17-Hydroxysteroid dehydrogenase and cancers, Journal of Steroid 643
558 istry 54 (2011) 4863–4879. Biochemistry and Molecular Biology 83 (2003) 119–122. 644
559 [24] M.P. Leese, F.L. Jourdan, K. Gaukroger, M.F. Mahon, S.P. Newman, P.A. Foster, [50] R. Mindnich, G. Moller, J. Adamski, The role of 17-hydroxysteroid dehydro- 645
560 C. Stengel, S. Regis-Lydi, E. Ferrandis, A.D. Fiore, G.D. Simone, C.T. Supu- genases, Molecular and Cellular Endocrinology 218 (2004) 7–20. 646
561 ran, A. Purohit, M.J. Reed, B.V.L. Potter, Structure–activity relationships of [51] F. Labrie, V. Luu, S.X. Lin, J. Simard, C. Labrie, M. El-Alfy, G. Pelletier, A. Belanger, 647
562 C-17 cyano-substituted estratrienes as anticancer agents, Journal of Medicinal Intracrinology: role of the family of 17-hydroxysteroid dehydrogenases in 648
563 Chemistry 51 (2008) 1295–1308. human physiology and disease, Journal of Molecular Endocrinology 25 (2000) 649
564 [25] J.E. Reed, L.W.L. Woo, J.J. Robinson, B. Leblond, M.P. Leese, A. Purohit, M.J. 1–16. 650
565 Reed, B.V.L. Potter, 2-Difluoromethyloestrone 3-O-sulfamate, a highly potent [52] J. Fomitcheva, M.E. Baker, E. Anderson, G.Y. Lee, N. Aziz, Characterization of Ke 651
566 steroid sulphatase inhibitor, Biochemical and Biophysical Research Commu- 6, a new 17-hydroxysteroid dehydrogenase, and its expression in gonadal 652
567 nications 317 (2004) 196–275. tissues, Journal of Biological Chemistry 273 (1998) 22664–22671. 653
568 [26] M.P. Leese, B. Leblond, A. Smith, S.P. Newman, A. Di Fiore, G. De Simone, [53] V. Luu, Analysis and characteristics of multiple types of human 17- 654
569 et al., 3,17-Disubstituted 2-alkylestra-1,3,5(10)-trien-3-ol derivatives: syn- hydroxysteroid dehydrogenase, Journal of Steroid Biochemistry and Molecu- 655
570 thesis, in-vitro and in-vivo anticancer activity, Journal of Medicinal Chemistry lar Biology 76 (2001) 143–151. 656
571 49 (2006) 7683–7696. [54] S. Nagasaki, T. Suzuki, Y. Miki, J. Akira, K. Kitada, T. Ishida, H. Handa, N. Ohuchi, 657
572 [27] L.C. Ciobanu, V. Luu, C. Martel, F. Labrie, D. Poirier, inhibition of estrone H. Sasano, 17-Hydroxysteroid dehydrogenase type 12 in human breast car- 658
573 sulfate-induced uterine growth by potent nonestrogenic steroidal inhibitors cinoma: a prognostic factor via potential regulation of fatty acid synthesis, 659
574 of steroid sulfatase, Cancer Research 63 (2003) 6442–6446. Cancer Research 69 (2009) 1392–1399. 660
575 [28] M.P. Leese, H.A.M. Hejaz, M.F. Mahon, S.P. Newman, A. Purohit, M.J. Reed, B.V.L. [55] K.K. Rasiah, M. Gardiner-Garden, E.J. Padilla, G. Moller, J.G. Kench, M.C. Alles, 661
576 Potter, A-ring-substituted estrogen-3-O-sulfamates: potent multitargeted S.A. Eggleton, P.D. Stricker, J. Adamski, R.L. Sutherland, S.M. Henshall, V.M. 662
577 anticancer agents, Journal of Medicinal Chemistry 48 (2005) 5243–5256. Hayes, HSD174 over-expression, an independent biomarker of poor patient 663
578 [29] L.M. Rasmussen, N.T. Zaveri, J. Stenvang, R.H. Peters, A.E. Lykkesfeldt, A outcome in prostate cancer, Molecular and Cellular Endocrinology 310 (2009) 664
579 novel dual-target steroid sulfatase inhibitor and antiestrogen: SR 16157, a 89–96. 665
580 promising agent for the therapy of breast cancer, Breast Cancer Research and [56] M. Poutanen, V. Isomaa, V.P. Lehto, R. Vihko, Immunological analysis of 17- 666
581 Treatment 106 (2007) 191–203. hydroxysteroid dehydrogenase in benign and malignant human breast tissue, 667
582 [30] M.R. Waterman, Anticancer drug target pictured, Nature 457 (2009) 159–160. International Journal of Cancer 50 (1992) 386–390. 668
583 [31] S. Chumsri, T. Howes, T. Bao, G. Sabnis, A. Brodie, Aromatase, aromatase [57] P. Vihko, P. Harkonen, O. Oduwole, S. Torn, R. Kurkela, K. Porvari, A. Pulkka, V. 669
584 inhibitors and breast cancer, Journal of Steroid Biochemistry and Molecular Isomaa, 17-Hydroxysteroid dehydrogenases and cancers, Journal of Steroid 670
585 Biology 125 (2011) 13–22. Biochemistry and Molecular Biology 83 (2002) 119–122. 671
586 [32] D. Ghosh, J. Griswold, M. Erman, W. Pangborn, Structural basis for androgen [58] T.E. Spires, B.E. Fink, E.K. Kick, D. You, et al., Identification of novel func- 672
587 specificity and oestrogen synthesis in human aromatase, Nature 457 (2009) tional inhibitors of 17-hydroxysteroid dehydrogenase type-III (17-HSD3), 673
588 219–223. Prostate 65 (2005) 159–170. 674
589 [33] A.M.H. Brodie, W.M. Garrett, J.R. Handrickson, C.H. Tsai-Morris, P.A. Marcotte, [59] D. Poirier, P. Dionne, S. Auger, a 6-(thiaheptanamide) derivative of estradiol 675
590 C.H. Robinson, Inactivation of aromatase in vitro by 4-hydroxy-4-androstene- as inhibitor of 17-hydroxysteroid dehydrogenase type 1, Journal of Steroid 676
591 3,17-dione and 4-acetoxy-4-androstene-3,17-dione and sustained effects in Biochemistry and Molecular Biology 64 (1998) 83–90. 677
592 vivo, Steroids 38 (1981) 693–702. [60] C. Cadot, Y. Laplante, F. Kamal, V. Luu, D. Poirier, C6-(N,N-butyl-methyl- 678
593 [34] D. Poirier, New cancer drugs targeting the biosynthesis of estrogens and heptanamide) derivatives of estrone and estradiol as inhibitors of type 1 679

594 androgens, Drug Development Research 69 (2008) 304–318. 17 -hydroxysteroid dehydrogenase: chemical synthesis and biological eval- 680
595 [35] S. Steckebroeck, D.D. Heidrich, B.S. Wagner, V.H. Hans, J. Schramm, F. Bidling- uation, Bioorganic and Medicinal Chemistry 15 (2007) 714–726. 681

596 maier, D. Klingmuller, Characterisation of aromatase cytochrome 450 in [61] D. Poirier, P. Bydal, M.R. Tremblay, K.M. Sam, V. Luu, Inhibitors of type II 17 - 682
597 human temporal lobe, Journal of Clinical Endocrinology and Metabolism 84 hydroxysteroid dehydrogenase, Molecular and Cellular Endocrinology 171 683
598 (1999) 2795–2801. (2001) 119–128. 684

599 [36] P. Lombardi, Exemestane, a new steroidal aromatase inhibitor of clinical rel- [62] P. Bydal, S. Auger, D. Poirier, Inhibition of type 2 17 -hydroxysteroid 685
600 evance, Biochimica et Biophysica Acta 1587 (2002) 326–337. dehydrogenase by estradiol derivatives bearing a lactone on the D-ring: 686
601 [37] M.R. Yadav, P.M. Sabale, R. Giridhar, C. Zimmer, J. Haupenthal, R.W. Hart- structure–activity relationships, Steroids 69 (2004) 325–342. 687
602 mann, Synthesis of some novel androstanes as potential aromatase inhibitors, [63] H. Lawrence, H. Vicker, N. Allan, G.M. Smith, A. Mahon, M. Tutill, H.J. Puro- 688

603 Steroids 76 (2011) 464–470. hit, A. Reed, M.J. Reed, B.V.L. Potter, Novel and potent 17 -hydroxysteroid 689
604 [38] S. Komatsu, A. Yaguchi, K. Yamashita, M. Nagaoka, M. Numazawa, 6,19- dehydrogenase type 1 inhibitors, Journal of Medicinal Chemistry 48 (2005) 690
605 Bridged androstenedione analogs as aromatase inhibitors, Steroids 74 (2009) 2759–2762. 691
606 884–889. [64] D. Poirier, R.P. Boivin, M.R. Tremblay, M. Berube, W. Qiu, S.X. Lin, Estradiol- 692
607 [39] M. Numazawa, M. Ando, Y. Watari, T. Tominaga, Y. Hayata, A. Yoshimura, adenosine hybrid compounds designed to inhibit type 1, 17-hydroxysteroid 693
608 Journal of Steroid Biochemistry and Molecular Biology 96 (2005) 51–58. dehydrogenase, Journal of Medicinal Chemistry 48 (2005) 8134–8147. 694
609 [40] M.J. Balunas, B. Su, S. Riswan, H.H.S. Fong, R.W. Brueggemeier, J.M. Pez- [65] M. Berube, D. Poirier, Synthesis of simplified hybrid inhibitors of type 1 695
610 zuto, A.D. Kinghorn, Isolation and characterization of aromatase inhibitors 17-hydroxysteroid dehydrogenase via cross metathesis and sonogashira 696
611 from Brassaiopsis glomerulata (Araliaceae), Phytochemistry Letters 2 (2009) coupling reactions, Organic Letters 6 (2004) 3127–3130. 697
612 29–33. [66] B.T. Ngatcha, V. Luu, F. Labrie, D. Poirier, Androsterone 3␣-ether-3- 698
␣
613 [41] M. Numazawa, M. Oshibe, Further studies on 6-alkylandrost-4-ene-3,17- substituted and androsterone 3 -substituted derivatives as inhibitors of type 699
␣
614 diones as aromatase inhibitors: elongation of the 6-alkyl chain, Steroids 60 3 17 -hydroxysteroid dehydrogenase: chemical synthesis and structure- 700
615 (1995) 506–511. activity relationship, Journal of Medicinal Chemistry 48 (2005) 5257–5268. 701
Please cite this article in press as: A. Gupta, et al., Current status on development of steroids as anticancer agents, J. Steroid Biochem. Mol. Biol.
(2013), http://dx.doi.org/10.1016/j.jsbmb.2013.05.011
G Model
SBMB 3991 1–29 ARTICLE IN PRESS
A. Gupta et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2013) xxx–xxx 27
702 [67] B. Husen, K. Huhtinen, T. Saloniemi, J. Messinger, H.H. Thole, M. Poutanen, [90] L. Misra, P. Lal, N.D. Chaurasia, R.S. Sangwan, S. Sinha, R. Tuli, Selective reac- 788
703 Human hydroxysteroids dehydrogenase 1 expression enhances estrogen sen- tivity of 2-mercaptoethanol with 5,6-epoxide in steroids from Withania 789
704 sitivity of MCF-7 breast cancer cell xenografts, Endocrinology 147 (2006) somnifera, Steroids 73 (2008) 245–251. 790
705 5333–5339. [91] A.K. Samadi, X. Tong, R. Mukerji, H. Zhang, B.N. Timmermann, M.S. Cohen, 791
706 [68] D. Deluka, G. Moller, A. Rosinus, W. Elger, A. Hillisch, J. Adamski, Withaferin A, a cytotoxic steroid from Vassobia breWiflora, induces apoptosis 792
707 Inhibitory effects of fluorine-substituted estrogens on the activity of 17- in human head and neck squamous cell carcinoma, Journal of Natural Products 793
708 hydroxysteroid dehydrogenases, Molecular and Cellular Endocrinology 248 73 (2010) 1476–1481. 794
709 (2006) 218–224. [92] S. Boonananwong, B. Kongkathip, N. Kongkathip, First synthesis of 3,16,20- 795
710 [69] G.M. Allan, C. Bubert, N. Vicker, A. Smith, H.J. Tutill, A. Purohit, M.J. Reed, B.V.L. polyoxygenated cholestanes, new cytotoxic steroids from the gorgonian 796
711 Potter, Novel, potent inhibitors of 17-hydroxysteroid dehydrogenase type Leptogorgia sarmentosa, Steroids 73 (2008) 1123–1127. 797
712 1, Molecular and Cellular Endocrinology 248 (2006) 204–207. [93] N.V. Ivanchina, A.A. Kicha, V.A. Stonik, Steroid glycosides from marine organ- 798
713 [70] D. Poirier, H.J. Chang, A. Azzi, R.P. Boivin, S.X. Lin, Estrone and estradiol C- isms, Steroids 76 (2011) 425–454. 799
714 16 derivatives as inhibitors of type 1 17-hydroxysteroid dehydrogenase, [94] J. Malıkova, J. Swaczynova, Z. Kolar, M. Strnad, Anticancer and antiprolifera- 800
715 Molecular and Cellular Endocrinology 248 (2006) 236–238. tive activity of natural brassinosteroids, Phytochemistry 69 (2008) 418–426. 801
716 [71] F. Rouillard, J. Lefebvre, M.A. Fournier, D. Poirier, Chemical synthesis, 17- [95] V.M. Dembitsky, Bioactive peroxides as potential therapeutic agents, Euro- 802
717 hydroxysteroid dehydrogenase type 1 inhibitory activity and assessment in pean Journal of Medical Chemistry 43 (2008) 223–251. 803
718 in-vitro and in-vivo estrogenic activities of estradiol derivatives, The Open [96] S. Piacente, M. Masullo, N.D. Neve, J. Dewelle, A. Hamed, R. Kiss, T. Mijatovic, 804
719 Enzyme Inhibition Journal 1 (2008) 61–71. Cardenolides from Pergularia tomentosa display cytotoxic activity resulting 805
720 [72] M. Majumdar, D. Fournier, D.W. Zhu, C. Cadot, D. Poirier, S.X. Lin, Binary from their potent inhibition of Na+/K+-ATPase, Journal of Natural Products 806
721 and ternary crystal structure of a novel inhibitor with 17-HSD type 1: a 72 (2009) 1087–1091. 807
722 lead compound for breast cancer therapy, Biochemistry Journal 424 (2009) [97] S.B. Wu, Y.P. Ji, J.-J. Zhu, Y. Zhao, G. Xia, Y.H. Hu, J.F. Hu, Steroids from the leaves 808
723 357–366. of Chinese Melia azedarach and their cytotoxic effects on human cancer cell 809
724 [73] P. Bydal, V. Luu, F. Labrie, D. Poirier, Steroidal lactones as inhibitors of 17- lines, Steroids 74 (2009) 761–765. 810
725 hydroxysteroid dehydrogenase type5: chemical synthesis, enzyme inhibitory [98] N. Huu Tung, C.V. Minh, T.T. Ha, P.V. Kiem, H.T. Huong, N.T. Dat, N.X. Nhiem, 811
726 activity and assessment of estrogenic and androgenic activities, European B.H. Tai, J.H. Hyun, H.K. Kang, Y.H. Kim, C29 sterols with a cyclopropane ring 812
727 Journal of Medical Chemistry 44 (2009) 632–644. at C-25 and 26 from the Vietnamese marine sponge Ianthella sp. and their 813
728 [74] G. Moller, D. deluca, C. Gege, A. Rosinus, D. Kowalik, O. Peters, P. Droescher, anticancer properties, Bioorganic and Medicinal Chemistry Letters 19 (2009) 814
729 W. Elger, J. Adamski, A. Hillisch, Structure-based design, synthesis and 4584–4588. 815
730 in vitro characterization of potent 17-hydroxysteroid dehydrogenase type [99] L.W. Qi, C.Z. Wang, C.S. Yuan, American ginseng: potential structure–function 816
731 1 inhibitors based on 2-substitutions of estrone and D-homo-estrone, Bioor- relationship in cancer chemoprevention, Biochemical Pharmacology 80 817
732 ganic and Medicinal Chemistry Letters 19 (2009) 6740–6744. (2010) 947–954. 818
733 [75] S. Ray, I. Dwivedy, Development of estrogen antagonists as pharmaceutical [100] A.S. Lin, S. Engel, B.A. Smith, C.R. Fairchild, W. Aalbersberg, M.E. Hay, J. 819
734 agents, Advances in Drug Research 29 (1997) 171–270. Kubanek, Structure and biological evaluation of novel cytotoxic sterol gly- 820
735 [76] A. Claussner, L. Nedelec, F. Nique, D. Philibert, G. Teutsch, P. Van de Velde, cosides from the marine red alga Peyssonnelia sp, Bioorganic and Medicinal 821

736 11- -Amidoalkyl estradiols, a new series of pure antiestrogens, Journal of Chemistry 18 (2010) 8264–8269. 822
737 Steroid Biochemistry and Molecular Biology 41 (1992) 609–614. [101] R. Gasper, T. Mijatovic, A. Bénard, A. Derenne, R. Kiss, E. Goormaghtigh, FTIR 823
738 [77] V. Agouridas, E. Magnier, J.C. Blazejewski, I. Laios, A. Cleeren, D. Nonclercq, spectral signature of the effect of cardiotonic steroids with antitumoral prop- 824
739 G. Laurent, G. Leclercq, Effect of fluorination on the pharmacological profile erties on a prostate cancer cell line, Biochimica et Biophysica Acta 1802 (2010) 825

740 of 11 -isomers of fulvestrant in breast carcinoma cells, Journal of Medicinal 1087–1094. 826
741 Chemistry 52 (2009) 883–887. [102] Z.W. Xu, F.M. Wang, M.J. Gao, X.Y. Chen, N.N. Shan, S.X. Cheng, X. Mai, G.H. 827
742 [78] F. Nique, P. Van de Velde, J. Brémaud, M. Hardy, D. Philibert, G. Teutsch, 11- Zala, W.L. Hu, R.C. Xu, Cardiotonic steroids attenuate ERK phosphorylation 828
743 Amidoalkoxyphenyl estradiols, a new series of pure antiestrogens, Journal of and generate cell cycle arrest to block human hepatoma cell growth, Journal 829
744 Steroid Biochemistry and Molecular Biology 50 (1994) 21–29. of Steroid Biochemistry and Molecular Biology 125 (2011) 181–191. 830
745 [79] A.E. Wakeling, J. Bowler, ICI 182,780, a new antiestrogen with clinical [103] L.J. Rashan, K. Franke, M.M. Khine, G. Kelter, H.H. Fiebig, J. Neumann, L.A. 831
746 potential, Journal of Steroid Biochemistry and Molecular Biology 43 (1992) Wessjohann, Characterization of the anticancer properties of monoglycosidic 832
747 173–177. cardenolides isolated from Nerium oleander and Streptocaulon tomentosum, 833
748 [80] E.C. Svensson, E. Markstrom, R. Shao, M. Andersson, H. Billig, Proges- Journal of Ethnopharmacology 134 (2011) 781–788. 834
749 terone receptor antagonists ORG 31710 and RU 486 increase apoptosis [104] J. Steigerova, L. Rarova, J. Oklest’kova,ˇ K. Krizova, M. Levkova, M. Svachova,ˇ Z. 835
750 in human periovulatory granulosa cells, Fertility and Sterility 76 (2001) Kolar, M. Strnad, Mechanisms of natural brassinosteroid-induced apoptosis 836
751 1225–1231. of prostate cancer cells, Food and Chemical Toxicology 50 (2012) 4068–4076. 837
752 [81] Q. Xu, S. Takekida, N. Ohara, W. Chen, R. Sitruk-Ware, E.D. Johansson, T. Maruo, [105] Q.Y. Tong, Y. He, Q.B. Zhao, Y. Qing, W. Huang, X.H. Wu, Cytotoxicity and 838
753 Progesterone receptor modulator CDB-2914 down-regulates proliferative cell apoptosis-inducing effect of steroidal saponins from Dioscorea zingiberensis 839
754 nuclear antigen and Bcl-2 protein expression and up-regulates caspase-3 Wright against cancer cells, Steroids 77 (2012) 1219–1227. 840
755 and poly(adenosine 5 -diphosphate-ribose) polymerase expression in cul- [106] M.J. Manase, A.C.M. Offer, D. Pertuit, T. Miyamoto, C. Tanaka, S. Delemasure, P. 841
756 tured human uterine leiomyoma cells, Journal of Clinical Endocrinology and Dutartre, J.F. Mirjolet, O. Duchamp, M.A.L. Dubois, Solanum incanum and S. het- 842
757 Metabolism 90 (2005) 953–961. eracanthum as sources of biologically active steroid glycosides: confirmation 843
758 [82] H.J. Kloosterboer, G.H. Deckers, W.G. Schoonen, R.G. Hanssen, U.M. Rose, P.M. of their synonymy, Fitoterapia 83 (2012) 1115–1119. 844
759 Verbost, J.G. Hsiu, R.F. Williams, G.D. Hodgen, Preclinical experience with [107] K. Arpha, C. Phosri, N. Suwannasai, W. Mongkolthanaruk, S. Sodngam, 845
760 two selective progesterone receptor modulators on breast and endometrium, Astraodoric acids A–D: new lanostane triterpenes from edible mushroom 846
761 Steroids 65 (2000) 733–740. Astraeus odoratus and their anti-Mycobacterium tuberculosis H37Ra and 847
762 [83] R.D. Wiehle, K. Christov, R. Mehta, Anti-progestins suppress the growth of cytotoxic activity, Journal of Agricultural and Food Chemistry 60 (2012) 848
763 established tumors induced by 7,12-dimethylbenz(a)anthracene: compari- 9834–9841. 849
764 son between RU486 and a new 21-substituted-19-nor-progestin, Oncology [108] M. Cushman, H.M. He, J.A. Katzenellenbogen, R.K. Varma, E. Hamel, C.M. 850
765 Reports 18 (2007) 167–174. Lin, S. Ram, Y.P. Sachdeva, Synthesis of analogs of 2-methoxyestradiol with 851
766 [84] A.A. Goyeneche, E.E. Seidel, C.M. Telleria, Growth inhibition induced by enhanced inhibitory effects on tubulin polymerization and cancer cell growth, 852
767 antiprogestins RU-38486, ORG-31710, and CDB-2914 in ovarian cancer cells Journal of Medicinal Chemistry 40 (1997) 2323–2334. 853
768 involves inhibition of cyclin dependent kinase 2, Investigational New Drugs [109] M. Nakamura, Y. Katsuki, Y. Shibutani, T. Oikawa, Dienogest a synthetic 854
769 30 (2012) 967–980. steroid, suppresses both embryonic and tumor-cell-induced angiogenesis, 855
770 [85] W. Afhuppe, J.M. Beekman, C. Otto, J. Hoffmann, U. Fuhrmann, C. Moller, European Journal of Pharmacology 386 (1999) 33–40. 856
771 In vitro characterization of ZK 230211—a type III progesterone receptor [110] Z. Wang, D. Yang, A.K. Mohanakrishnan, P.E. Fanwick, P. Nampoothiri, E. 857
772 antagonist with enhanced antiproliferative properties, Journal of Steroid Bio- Hamel, M. Cushman, Synthesis of B-ring homologated estradiol analogues 858
773 chemistry and Molecular Biology 119 (2010) 45–55. that modulate tubulin polymerization and microtubule stability, Journal of 859
774 [86] Y. Hayakawa, K. Furihata, K. Shin-ya, T. Mori, Gymnasterol, a new antitumor Medicinal Chemistry 43 (2000) 2419–2429. 860
775 steroid against IGF-dependent cells from Gymnascella dankaliensis, Tetrahe- [111] W. Xie, H. Peng, D. Kim, M. Kunkel, G. Powis, L.H. Zalkow, Structure activity 861
776 dron Letters 44 (2003) 1165–1166. relationship of Aza steroids as PI-PLC inhibitors, Bioorganic and Medicinal 862
777 [87] X. Hea, B. Liuc, G. Wang, X. Wang, L. Sud, G. Qud, X. Yao, Microbial metabolism Chemistry 9 (2001) 1073–1083. 863
778 of methyl protodioscin by Aspergillus niger culture—a new androstenedione [112] D. Milic, T. Kop, Z. Juranic, M.J. Gasic, B. Tinant, G. Pocsfalvi, B.A. Solaja, 864
779 producing way from steroid, Journal of Steroid Biochemistry and Molecular Synthesis antiproliferative activity of A-ring aromatized and conduritol-like 865
780 Biology 100 (2006) 87–94. steroidal compounds, Steroids 70 (2005) 922–932. 866
781 [88] P.C. Kuo, T.H. Kuo, A.G. Damu, C.R. Su, E.J. Lee, T.S. Wu, R. Shu, C.M. Chen, [113] X. He, J. Tang, A. Qiao, G. Wang, M. Jiang, R.H. Liu, X. Yao, Cytotoxic biotrans- 867
782 K.F. Bastow, T.H. Chen, K.H. Lee, A. Physanolide, A novel skeleton steroid, and formed products from cinobufagin by Mucor spinosus and Aspergillus niger, 868
783 other cytotoxic principles from Physalis angulata, Organic Letters 8 (2006) Steroids 71 (2006) 392–402. 869
784 2953–2956. [114] G. Berube, D. Rabouin, V. Perron, B. N’Zemba, R.C. Gaudreault, S. Parent, E. 870

785 [89] I. Kontiza, D. Abatis, K. Malakate, C. Vagias, V. Roussis, 3-Keto steroids from the Asselin, Synthesis of unique 17 -estradiol homo-dimers, estrogen receptors 871
786 marine organisms Dendrophyllia cornigera and Cymodocea nodosa, Steroids 71 binding affinity evaluation and cytocidal activity on breast, intestinal and skin 872
787 (2006) 177–181. cancer cell lines, Steroids 71 (2006) 911–921. 873
Please cite this article in press as: A. Gupta, et al., Current status on development of steroids as anticancer agents, J. Steroid Biochem. Mol. Biol.
(2013), http://dx.doi.org/10.1016/j.jsbmb.2013.05.011
G Model
SBMB 3991 1–29 ARTICLE IN PRESS
28 A. Gupta et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2013) xxx–xxx
874 [115] H.O. Saxena, U. Faridi, J.K. Kumar, S. Luqman, M.P. Darokar, K. Shanker, of withaferin A and the evaluation of their cytotoxic potential, Steroids 76 960
875 C.S. Chanotiya, M.M. Gupta, A.S. Negi, Synthesis of chalcone derivatives (2011) 1213–1222. 961
876 on steroidal framework and their anticancer activities, Steroids 72 (2007) [138] M.I. Choudhary, M.S. Alam, A. Rahman, S. Yousuf, Y.C. Wu, A.S. Lin, F. Shaheen, 962
877 892–900. Pregnenolone derivatives as potential anticancer agents, Steroids 76 (2011) 963
878 [116] R. Bansal, S. Guleria, Synthesis of 16E-[3-methoxy-4-(2-aminoethoxy)- 1554–1559. 964
879 benzylidene]androstene derivatives as potent cytotoxic agents, Steroids 73 [139] D. Kovacs, Z. Kadar, G. Mótyán, G. Schneider, J. Wölfling, I. Zupkó, É. Frank, Syn- 965
880 (2008) 1391–1399. thesis, characterization and biological evaluation of some novel 17-isoxazoles 966
881 [117] V.M.A. Moreira, T.S. Vasaitis, Z. Guo, V.C.O. Njar, J.A.R. Salvador, Synthesis of in the estrone series, Steroids 77 (2012) 1075–1085. 967
882 novel C17 steroidal carbamates Studies on CYP17 action, androgen receptor [140] R. Bansal, P.C. Acharya, Synthesis and antileukemic activity of 16E- 968
883 binding and function, and prostate cancer cell growth, Steroids 73 (2008) [4-(2-carboxy)ethoxybenzylidene]-androstene amides, Steroids 77 (2012) 969
884 1217–1227. 552–557. 970
885 [118] L.E. Kihel, M. Clément, M.A. Bazin, G. Descamps, M. Khalid, S. Rault, New [141] Y. Li, J. Huang, J. Liu, P. Yan, H. Liu, Q. Sun, X. Wang, C. Wang, Synthesis and 971
886 lithocholic and chenodeoxycholic piperazinylcarboxamides with antiprolif- cytotoxicity of 17E-(2-aryl-2-oxo-1-ethylidene)-5a-androstane derivatives, 972
887 erative and pro-apoptotic effects on human cancer cell lines, Bioorganic and Steroids 76 (2011) 1615–1620. 973
888 Medicinal Chemistry 16 (2008) 8737–8744. [142] N.M. Krstic, M.S. Bjelakovic, V.D. Pavlovic, K. Robeyns, Z.D. Juranic, 974
889 [119] M.J. Kaskiw, M.L. Tassotto, M. Moka, S.L. Tokar, R. Pycko, J. Th’ng, Z.H. Jiang, I. Matic, I. Novakovic, D.M. Sladic, New androst-4-en-17-spiro-1,3,2- 975
890 Structural analogues of diosgenyl saponins: synthesis and anticancer activity, oxathiaphospholanes. Synthesis, assignment of absolute configuration 976
891 Bioorganic and Medicinal Chemistry 17 (2009) 7670–7679. and in vitro cytotoxic and antimicrobial activities, Steroids 77 (2012) 977
892 [120] J. Roy, P. DeRoy, D. Poirier, 2-(N-substituted piperazino)-5␣-androstane- 558–565. 978
893 3␣,17-diols: parallel solid-phase synthesis and antiproliferative activity on [143] Z. Iványi, N. Szabo, J. Huber, J. Wolfling, I. Zupko, M. Szécsi, T. Wittmann, 979
894 human leukemia HL-60 cells, Journal of Combinatorial Chemistry 9 (2007) G. Schneider, Synthesis of D-ring-substituted (50R)- and (50S)-17b- 980
895 347–358. pyrazolinylandrostene epimers and comparison of their potential anticancer 981
896 [121] B. Slavikova, L. Kohout, M. Budesinsky, J. Swaczynova, A. Kasal, Brassinos- activities, Steroids 77 (2012) 566–574. 982
897 teroids, Synthesis and activity of some fluoro analogues, Journal of Medicinal [144] L.H. Huang, Y.F. Zheng, Y.Z. Lu, C.J. Song, Y.G. Wang, B. Yu, H.M. Liu, Syn- 983
898 Chemistry 51 (2008) 3979–3984. thesis and biological evaluation of novel steroidal[17,16-d][1,2,4]triazolo 984
899 [122] A.Y. Misharina, A.R. Mehtieva, V.N. Zhabinskiib, V.A. Khripachb, V.P. Tim- [1,5-a]pyrimidines, Steroids 77 (2012) 710–715. 985
900 ofeevc, Y.V. Tkachev, Toxicity of (22R,23R)-22,23-dihydroxystigmastane [145] S. Parihar, A. Gupta, A.K. Chaturvedi, J. Agarwal, S. Luqman, B. Changkija, M. 986
901 derivatives to cultured cancer cells, Steroids 75 (2010) 287–294. Manohar, D. Chanda, C.S. Chanotiya, K. Shanker, A. Dwivedi, R. Konwar, A.S. 987
902 [123] P. Bunyathaworn, S. Boonananwong, B. Kongkathip, N. Kongkathip, Further Negi, Gallic acid based steroidal phenstatin analogues for selective targeting 988
903 study on synthesis and evaluation of 3,16,20-polyoxygenated steroids of of breast cancer cells through inhibiting tubulin polymerization, Steroids 77 989
904 marine origin and their analogs as potent cytotoxic agents, Steroids 75 (2010) (2012) 878–886. 990
905 432–444. [146] H. Jegham, R. Maltais, P. Dufour, J. Roy, D. Poirier, Solid-phase chemical 991
906 [124] A.H. Banday, S.A. Shameem, B.D. Gupta, H.M. Sampath Kumar, D-ring sub- synthesis and in vitro biological evaluation of novel 2-piperazino-(20R)- 992
907 stituted 1,2,3-triazolyl 20-keto pregnenanes as potential anticancer agents: 5␣-pregnane-3␣,20-diol N-derivatives as anti-leukemic agents, Steroids 77 993
908 synthesis and biological evaluation, Steroids 75 (2010) 801–804. (2012) 1403–1418. 994
909 [125] C. Li, W. Qiu, Z. Yang, J. Luo, F. Yang, M. Liu, J. Xie, J. Tang, Stereoselective [147] L. Rarova, S. Zahler, J. Liebl, V. Krystof, D. Sedlak, P. Bartunek, L. Kohout, M. 995
910 synthesis of some methyl-substituted steroid hormones and their in vitro Strnad, Brassinosteroids inhibit in vitro angiogenesis in human endothelial 996
911 cytotoxic activity against human gastric cancer cell line MGC-803, Steroids cells, Steroids 77 (2012) 1502–1509. 997
912 75 (2010) 859–869. [148] R.M. Mohareb, F. Al-Omran, Reaction of pregnenolone with cyanoacetyl- 998
913 [126] H. Guo, G. Zhang, T. Zhang, X. He, Z. Wu, Y. Xiao, Y. Pan, G. Qiu, P. Liu, hydrazine: novel synthesis of hydrazide–hydrazone, pyrazole, pyridine, 999
914 X. Hu, Synthesis, characterization and biological evaluation of some 16- thiazole, thiophene derivatives and their cytotoxicity evaluations, Steroids 1000
915 azolyl-3amino-5␣-androstane derivatives as potential anticancer agents, 77 (2012) 1551–1559. 1001
916 European Journal of Medical Chemistry 46 (2011) 3662–3674. [149] G.G.L. Lanos, L.M. Araujo, I.A. Jiménez, L.M. Moujir, I.L. Bazzocchi, Withaferin 1002
917 [127] M.A. Fernández-Herrera, H. López-Munoz,˜ J.M.V. Hernández-Vázquez, A-related steroids from Withania aristata exhibit potent antiproliferative 1003
918 M. López-Dávila, S. Mohan, M.L. Escobar-Sánchez, L. Sánchez-Sánchez, activity by inducing apoptosis in human tumor cells, European Journal of 1004
919 B.M. Pinto, J. Sandoval-Ramírez, Synthesis and biological evaluation Medical Chemistry 54 (2012) 499–511. 1005
920 of the glycoside (25R)-3,16-diacetoxy-22-oxocholest-5-en-26-yl -d- [150] H. Shamsuzzaman, A.M. Khanam, N. Dar, S. Siddiqui, Rehman, Syn- 1006
921 glucopyranoside: a selective anticancer agent in cervicouterine cell lines, thesis, characterization, antimicrobial and anticancer studies of 1007
922 European Journal of Medical Chemistry 46 (2011) 3877–3886. new steroidal pyrazolines, Journal of Saudi Chemical Society (2012), 1008
923 [128] M.A. Fernández-Herrera, H. López-Munoz,˜ J.M.V. Hernández-Vázquez, M. http://dx.doi.org/10.1016/j.jscs.2012.05.004. 1009
924 López-Dávila, M.L. Escobar-Sánchez, L. Sánchez-Sánchez, B.M. Pinto, J. [151] T.F. Liu, X. Lu, H. Tang, M.M. Zhang, P. Wang, P. Sun, Z.Y. Liu, Z.L. Wang, L. Li, Y.C. 1010
925 Sandoval-Ramírez, Synthesis of 26-hydroxy-22-oxocholestanic frameworks Rui, T.J. Li, W. Zhang, 3,5␣,6-Oxygenated sterols from the South China Sea 1011
926 from diosgenin and hecogenin and their in vitro antiproliferative and apop- gorgonian Muriceopsis flavida and their tumor cell growth inhibitory activity 1012
927 totic activity on human cervical cancer CaSki cells, Bioorganic and Medicinal and apoptosis-inducing function, Steroids 78 (2013) 108–114. 1013
928 Chemistry 18 (2010) 2474–2484. [152] A. Berenyi, R. Minorics, Z. Ivanyi, I. Ocsovszki, E. Ducza, H. Thole, J. Messinger, 1014
929 [129] M. Jensen, S. Schmidt, N.U. Fedosova, J. Mollenhauer, H.H. Jensen, Synthe- J. Wolfling, G. Motyan, E. Mernyak, E. Frank, G. Schneider, I. Zupko, Synthesis 1015
930 sis and evaluation of cardiac glycoside mimics as potential anticancer drugs, and investigation of the anticancer effects of estrone-16-oxime ethers in vitro, 1016
931 Bioorganic and Medicinal Chemistry 19 (2011) 2407–2417. Steroids 78 (2013) 69–78. 1017
932 [130] G.A. Elmegeed, W.K.B. Khalil, R.M. Mohareb, H.H. Ahmed, M.M. Abd-Elhalim, [153] J. Ren, Y. Wang, J. Wang, J. Lin, K. Wei, R. Huang, Synthesis and antitumor 1018
933 G.H. Elsayed, Cytotoxicity and gene expression profiles of novel synthesized activity of N-sulfonyl-3,7-dioxo-5b-cholan-24-amides,ursodeoxycholic acid 1019
934 steroid derivatives as chemotherapeutic anti-breast cancer agents, Bioorganic derivatives, Steroids 78 (2013) 53–58. 1020
935 and Medicinal Chemistry 19 (2011) 6860–6872. [154] S. Parihar, A. Kumar, A.K. Chaturvedi, N.K. Sachan, S. Luqman, B. Changk- 1021
936 [131] J.F.S. Carvalho, M.M.C. Silva, J.N. Moreira, S. Simoes, M.L.S. Melo, Sterols as ija, M. Manohar, O. Prakash, D. Chanda, F. Khan, C.S. Chanotiya, K. 1022
937 anticancer agents: synthesis of ring-B oxygenated steroids, cytotoxic profile, Shanker, A. Dwivedi, R. Konwar, A.S. Negi, Synthesis of combretastatin 1023
938 and comprehensive SAR analysis, Journal of Medicinal Chemistry 53 (2010) A4 analogues on steroidal framework and their anti-breast cancer activ- 1024
939 7632–7638. ity, Journal of Steroid Biochemistry and Molecular Biology 105 (2013), 1025
940 [132] A.H. Banday, B.P. Mir, I.H. Lone, K.A. Suri, H.M.S. Kumar, Studies on novel D- http://dx.doi.org/10.1016/j.jsbmb.2013.02.009. 1026
941 ring substituted steroidal pyrazolines as potential anticancer agents, Steroids [155] E.J. Derbyshire, Y.C. Yang, G.A. Comin, J. Belloir, P.E. Thorpe, Heparin-steroid 1027
942 75 (2010) 805–809. conjugates lacking glucocorticoids or mineralocorticoids activities inhibit the 1028
943 [133] R. Minorics, T. Szekeres, G. Krupitza, P. Saiko, B. Giessrigl, J. Wölfling, E. Frank, proliferation of vascular endothelial cells, Biochimica et Biophysica Acta 1310 1029
944 I. Zupko, Antiproliferative effects of some novel synthetic solanidine analogs (1996) 86–96. 1030
945 on HL-60 human leukemia cells in vitro, Steroids 76 (2011) 156–162. [156] R. Devraj, J.F. Barrett, J.A. Fernandez, J.A. Katzenellenbogen, M. Cushman, 1031
946 [134] R. Schobert, S. Seibt, K. Effenberger-Neidnicht, C. Underhill, B. Biersack, G.L. Design, synthesis, and biological evaluation of ellipticine–estradiol conju- 1032
947 Hammond, (Arene)Cl2Ru(II) complexes with N-coordinated estrogen and gates, Journal of Medicinal Chemistry 39 (1996) 3367–3374. 1033
948 androgen isonicotinates: interaction with sex hormone binding globulin and [157] C. Liu, J.S. Strobl, S. Bane, J.K. Schilling, M. McCracken, S.K. Chatterjee, R.R. 1034
949 anticancer activity, Steroids 76 (2011) 393–399. Bata, D.G.I. Kingston, Design, synthesis, and bioactivities of steroid-linked 1035
950 [135] H. Guo, H. Wu, J. Yang, Y. Xiao, H.J. Altenbach, G. Qiu, H. Hu, Z. Wu, X. He, taxol analogues as potential targeted drugs for prostate and breast cancer, 1036
951 D. Zhou, X. Hu, Synthesis, characterization and biological evaluation of some Journal of Natural Products 67 (2004) 152–159. 1037
952 16E-arylidene androstane derivatives as potential anticancer agents, Steroids [158] A. Gupta, P. Saha, C. Descoteaux, V. Leblanc, E. Asselin, G. Berube, Design, 1038
953 76 (2011) 709–723. synthesis and biological evaluation of estradiol–chlorambucil hybrids as 1039
954 [136] G. Panchapakesan, V. Dhayalan, N.D. Moorthy, N. Saranya, A.K. Mohanakrish- anticancer agents, Bioorganic and Medicinal Chemistry Letters 20 (2010) 1040
955 nan, Synthesis of 2-substituted 17b-hydroxy/17-methylene estratrienes and 1614–1618. 1041
956 their in vitro cytotoxicity in human cancer cell cultures, Steroids 76 (2011) [159] S. Adsule, S. Banerjee, F. Ahmed, S. Padhye, F.H. Sarkar, Hybrid anticancer 1042
957 1491–1504. agents: isothiocyanate–progesterone conjugates as chemotherapeutic agents 1043
958 [137] S.K. Yousuf, R. Majeed, M. Ahmad, P.L. Sangwan, B. Purnima, A.K. Saxsena, and insights into their cytotoxicities, Bioorganic and Medicinal Chemistry 1044
959 K.A. Suri, D. Mukherjee, S.C. Taneja, Ring A structural modified derivatives Letters 20 (2010) 1247–1251. 1045
Please cite this article in press as: A. Gupta, et al., Current status on development of steroids as anticancer agents, J. Steroid Biochem. Mol. Biol.
(2013), http://dx.doi.org/10.1016/j.jsbmb.2013.05.011
G Model
SBMB 3991 1–29 ARTICLE IN PRESS
A. Gupta et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2013) xxx–xxx 29
1046 [160] L.H. Huang, Y.G. Wang, G. Xu, X.H. Zhang, Y.F. Zheng, H.L. He, W.Z. Fu, H.M. Liu, affinity of novel estradiol-linked platinum(II) complex analogs to carboplatin 1059
1047 Novel 4-azasteroidal N-glycoside analogues bearing sugar-like D ring: syn- and oxaliplatin. Potential vector complexes to target estrogen-dependent tis- 1060
1048 thesis and anticancer activities, Bioorganic and Medicinal Chemistry Letters sues, European Journal of Medical Chemistry 48 (2012) 385–390. 1061
1049 21 (2011) 6203–6205. [164] M.A. Fernandez-Herrera, H. Lopez-Munoz, J.M.V. Hernandez-Vazquez, L. 1062
1050 [161] A. Kamal, M.K. Reddy, M.J. Ramaiah, R.J.S. Reddy, Y.V.V. Srikanth, D. Dasagiri, Sanchez-Sanchez, M.L. Escobar-Sanchez, B.M. Pinto, J. Sandoval-Ramirez, 1063
1051 E.V. Bharthi, S.N.C.V.L. Pushpavalli, P. Sharma, M. Pal-Bhadra, Synthesis and Synthesis and selective anticancer activity of steroidal glycoconjugates, Euro- 1064
1052 Biological evaluation of estradiol linked pyrrolo [2,1-c]-[1,4]-benzodiazepine pean Journal of Medical Chemistry 54 (2012) 721–727. 1065
1053 (PBD) conjugates as potential anticancer agents, Bioorganic and Medicinal [165] P. Saha, S. Fortin, V. Leblanc, S. Parent, E. Asselin, G. Berube, Design, synthesis, 1066
1054 Chemistry 19 (2011) 2565–2581. cytocidal activity and estrogen receptor a affinity of doxorubicin conjugates 1067
␣
1055 [162] J. Ruiz, V. Rodríguez, N. Cutillas, A. Espinosa, M.J. Hannon, A potent ruthe- at 16 -position of estrogen for site-specific treatment of estrogen receptor 1068
1056 nium(II) antitumor complex bearing a lipophilic levonorgestrel group, Journal positive breast cancer, Steroids 77 (2012) 1113–1122. 1069
1057 of Inorganic Chemistry 50 (2011) 9164–9171. [166] K.L. Dao, R.N. Hansen, Targeting the estrogen receptor using steroid- 1070
1058 [163] P. Saha, C. Descôteaux, K. Brasseur, S. Fortin, V. Leblanc, S. Parent, E. therapeutic drug conjugates (hybrids), Bioconjugate Chemistry 23 (2012) 1071
Asselin, G. Bérube, Synthesis antiproliferative activity and estrogen receptor ␣ 2129–2158. 1072
Please cite this article in press as: A. Gupta, et al., Current status on development of steroids as anticancer agents, J. Steroid Biochem. Mol. Biol.
(2013), http://dx.doi.org/10.1016/j.jsbmb.2013.05.011