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Current Status on Development of Steroids As Anticancer Agents G Model SBMB 3991 1–29 ARTICLE IN PRESS Journal of Steroid Biochemistry & Molecular Biology xxx (2013) xxx–xxx 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. (2013), http://dx.doi.org/10.1016/j.jsbmb.2013.05.011 G Model SBMB 3991 1–29 ARTICLE IN PRESS 2 A. Gupta et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2013) xxx–xxx 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. (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 3 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 (17HSDI) 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. 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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