Thiadiazole Derivatives As Anticancer Agents

Pharmacological Reports (2020) 72:1079–1100 https://doi.org/10.1007/s43440-020-00154-7 REVIEW Thiadiazole derivatives as anticancer agents Monika Szeliga1 Received: 15 June 2020 / Revised: 13 August 2020 / Accepted: 20 August 2020 / Published online: 3 September 2020 © The Author(s) 2020 Abstract In spite of substantial progress made toward understanding cancer pathogenesis, this disease remains one of the leading causes of mortality. Thus, there is an urgent need to develop novel, more efective anticancer therapeutics. Thiadiazole ring is a versatile scafold widely studied in medicinal chemistry. Mesoionic character of this ring allows thiadiazole-containing compounds to cross cellular membrane and interact strongly with biological targets. Consequently, these compounds exert a broad spectrum of biological activities. This review presents the current state of knowledge on thiadiazole derivatives that demonstrate in vitro and/or in vivo efcacy across the cancer models with an emphasis on targets of action. The infuence of the substituent on the compounds’ activity is depicted. Furthermore, the results from clinical trials assessing thiadiazole- containing drugs in cancer patients are summarized. Keywords Thiadiazole derivatives · Cancer · Anticancer therapy · Clinical trials Introduction antiparasitic, anti-infammatory and anticancer activities [2]. Due to the mesoionic nature, thiadiazoles are able to According to the most recent data provided by the Interna- cross the cellular membranes. Their relatively good lipo- tional Agency for Research on Cancer (IARC), 18.1 mil- solubility is most likely attributed to the presence of the sul- lion new cases and 9.6 million cancer deaths were regis- phur atom [3]. The thiadiazole-containing drugs, including tered worldwide in 2018 [1]. Due to the population aging diuretics acetazolamide and methazolamide or antibiotics and growth, the number of new cancer cases is expected cefazedone and cefazolin sodium, are already used in clinics. to increase. Although a substantial progress was made in Accumulating evidence has also revealed numerous thiadia- the understanding of molecular biology of particular cancer zole derivatives that display anticancer activities in various types, and numerous potential specifc therapeutic targets in vitro and in vivo models (summarized in Table 1). Moreo- were identifed in recent years, there is an urgent necessity ver, several thiadiazole-containing compounds have moved for the development of improved anticancer therapeutic into clinical trials either as single agents or in combination strategies. with existing anticancer drugs (summarized in Table 2). Thiadiazole is a fve-membered heterocyclic compound containing one sulfur and two nitrogen atoms. It occurs in nature in four isoforms: 1,2,3-thiadiazole, 1,2,4-thiadizaole, Derivatives of 1,2,3‑thiadiazole 1,2,5-thiadiazole and 1,3,4-thiadiazole (Fig. 1). Taking into account that thiadiazole is the bioisostere of pyrimidine Inhibitors of tubulin polymerization and oxadiazole, it is not surprising that compounds bearing this moiety present a broad spectrum of pharmacologi- Microtubules are cytoskeleton flamentous proteins built by cal properties, including antiviral, antibacterial, antifungal, tubulin. They are involved in numerous cellular processes such as intracellular transport, cell signaling, mitosis, cellular integrity and gene expression, but also contribute to * Monika Szeliga polarity and shape of cells. A growing body of evidence [email protected] documents anticancer activity of diferent heterocyclic com- 1 Department of Neurotoxicology, Mossakowski Medical pounds inhibiting tubulin polymerization [4]. Research Centre, Polish Academy of Sciences, 5 Pawinskiego Str, 02-106 Warsaw, Poland Vol.:(0123456789)1 3 1080 M. Szeliga 1 1 Cikotine et al. synthesized a series of 5-aryl-4-(5-sub- S S stituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles bear- 5 2 5 2 N N ing at the position 5 of the thiadiazole ring one of the fol- lowing groups: 4-MeOC6H4, 4-EtOC6H4, 4-MeC6H4 or 4 N 3 4 N 3 3,4-di-MeOC6H3 and either chloro- or ethyl- substituent 1,2,3-thiadiazole 1,2,4-thiadiazole at the position 5 of the dihydroxyphenyl moiety. Each of these derivatives tightly bound to Hsp90 (Fig. 2), and the 1 1 strongest binding (dissociation constant (Kd) of 4.8 nM) S S displayed compound 3b, bearing a 4-EtOC6H4 substituent 5 2 5 2 N N at position 5 of thiadiazole and a chlorine atom at position 5 of dihydroxyphenyl. Each of the derivatives signifcantly inhibited viability of both human cervical carcinoma HeLa 4 3 4 N N 3 1,2,5-thiadiazole 1,3,4-thiadiazole and osteosarcoma U2OS cells and the most potent inhibitor appeared to be compound 3e bearing 4-EtOC6H4 group at Fig. 1 Core structures of the thiadiazole isoforms occurring in nature. the position 5 of the thiadiazole ring and an ethyl substituent Sulphur and nitrogen atoms are marked as yellow or blue circles, at the position 5 of dihydroxyphenyl. The GI 50 values of this respectively compound were 0.70 μM for HeLa and 0.69 μM for U2OS cells, respectively. Of note, the other group of 5-aryl-4-(5- substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles bear- Wu and co-workers focused on analogs of the cis stilbene ing chloro-substituent at position 3 of the dihydroxyphenyl derivative combretastatin A-4 (CA-4), an anticancer agent moiety did not bind to Hsp90 and was a very weak inhibi- which binds to tubulin and inhibits microtubule polymeriza- tor of cancer cell viability. Most likely, the presence of this tion. Cis confguration of the double bond in olefn group chloro-substituent prevented the formation of the extensive and 3,4,5-trimethoxyphenyl group are crucial for the CA-4’s H-bonding network which in turn led to a lack of activity [7]. activity. The newly designed and synthetized analogs con- Three of the compounds, confirmed to bind Hsp90 tained 1,2,3-thiadiazole instead of the CA-4’s olefn group. most efectively, were subjected to further analysis. They They exhibited a diverse cytotoxicity against human myeloid exhibited antiproliferative activity against human colon leukemia HL-60 cell line, human colon adenocarcinoma cancer HCT-116 cells with GI50 values ranging from 3.2 HCT-116 cell line, and immortalized human microvascular to 4.6 μM. Treatment of HCT-116 cells with each of the endothelial (HMEC-1) cells. In all three cell lines, several compounds resulted in a depletion of Hsp90 client proteins, tested compounds presented cytotoxic activity similar to that CRAF, ERBB2 and CDK4, confrming that antiprolifera- of CA-4 or lower, but still considerable (IC50 ranging from tive activity was linked to the inhibition of Hsp90 activity. 13.4 to 86.6 nM). Of note, if the 3,4,5-trimethoxyphenyl was Furthermore, such treatment caused upregulation of Hsp27 at 4th position in 1,2,3-thiadiazole, six out of nine tested and Hsp72 expression, suggesting an induction of the heat compounds displayed signifcant activity in all three cell shock response. Moreover, an increase in PARP cleavage lines, while if this substituent was at 5th position, only one evoked by the tested compounds indicated the induction of out of nine compounds was cytotoxic. These compounds apoptosis [8]. inhibited tubulin polymerization with activities quantita- tively similar to those of CA-4 and arrested the cell cycle at Miscellaneous 1,2,3‑thiadiazole derivatives G2/M phase. Two of these derivatives signifcantly reduced tumor growth in mice S180 sarcoma model with the inhibi- Aside from the derivatives presented above, there are also tion rate comparable or even higher to that of CA-4 [5]. some other compounds containing 1,2,3-thiadiazole moiety which display an anticancer activity, but their molec- Inhibitors of Hsp90 ular targets remain unknown. Among a series of D-ring fused 1,2,3-thiadiazole dehydroepiandrosterone (DHEA) The other group of 1,2,3-thiadiazole derivatives appeared derivatives, the most potent compounds 22, 23 and 25 to block the activity of heat shock protein 90 (Hsp90). presented antitumor activity against human breast cancer Hsp90 displays a chaperone activity and controls the fold- T47D cells with IC 50 values ranging between 0.042 and ing of numerous proteins. Inhibition of its activity results 0.058 μM. These values were comparable to that of ref- in the degradation of several oncoproteins. A growing body erence drug adriamycin (IC 50 = 0.04 μM). Of note, com- of evidence shows that tumor cells are more susceptible to pound 25 possessed a considerable selectivity towards blocking of Hsp90 compared to normal cells, therefore, this T47D cells. Its activity against the other breast cancer protein seems to be a promising anticancer target [6]. cell lines, MDA-MB-231 and MCF-7, as well as human 1 3 Thiadiazole derivatives as anticancer agents as anticancer derivatives Thiadiazole Table 1 Summary of the anticancer activities of the thiadiazole derivatives in vitro and in vivo Class of compounds Target Outcome References Derivatives of 1,2,3-thiadiazole Analogs of combretastatin A-4 (CA-4) containing 1,2,3-thiadiazole Tubulin polymerization Decreased proliferation of human myeloid leukemia HL-60, colon adeno- [5] carcinoma HCT-116, immortalized human microvascular endothelial HMEC-1 cells; reduced tumor growth in mice S180 sarcoma model 5-Aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles Hsp90 Decreased viability of human cervical carcinoma HeLa and osteosarcoma [7] U2OS cells Decreased proliferation of colon adenocarcinoma HCT-116 cells; induction [8] of apoptosis

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