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Eleven new steroidal mono- and bis(semicarbazones)2a–e, 4d and 3a–e have been prepared starting from various 3-oxo-α,β-unsaturated steroids. Mono-semicarbazones 2a–e were further subjected to ethyl chloroacetate in boiling absolute ethanol but, instead of expected intramolecular cyclocondensation reaction products, the new carbazate esters 5a-e were obtained. The structures of all synthesized compounds and identification of each E/Z isomer were deduced by elemental analysis, HRMS, NMR, and IR spectroscopy. Preliminary screening for the cytotoxic activity in vitro of the new compounds has been conducted against three cancer cell lines, K562, Jurkat and HeLa cells. HeLa cells were the most sensitive while K562 cells were the least sensitive to the cytotoxic action of the novel steroid derivatives. Compounds 2e, 3c and 5e were found to have the best but still moderate cytotoxic effects. All tested compounds showed very weak antimicrobial activities. These results demonstrate that the replacement of thioxo group with carbonyl group in steroidal hydrazone derivatives resulted in decrease in their biological activity

U potrazi za biološki aktivnim jedinjenjima, počev od progesterona i 3-okso- α,β-nezasićenih androstenskih steroida, u okviru ove disertacije sintetisano je i potpuno okarakterisano pedeset novih derivata steroidnih hidrazona, od kojih po jedanaest tiosemikarbazona, tijadiazolina i semikarbazona, dvanaest tiazolidin-4-ona i pet karbazatnih estara. Po prvi put je urađena detaljna analiza stereohemije steroidnih hidrazona u položajima C-3/17 androstenskih, odnosno C-3/20 progesteronskih derivata. Struktura i stereohemija potvrđene su rezultatima rendgenske strukturne analize za tijadiazolin 7a, prvo okarakterisano steroidno jedinjenje koje sadrži šestočlani ugljenični prsten kondenzovan sa spiro-tijadiazolinskim prstenom, i tiazolidinon 9b-E, prvi steroidni derivat sa poznatom konfiguracijom dvostruke veze u položaju C-3 hidrazonotiazolidin- 4-onskog fragmenta. Sintetisana jedinjenja su ispoljila najjaču citotoksičnost prema HeLa ćelijama adenokarcinoma cerviksa i prema K562 ćelijama hronične mijeloidne leukemije, a po svojoj aktivnosti istakli su se tiosemikarbazoni 2a, 2b, 2c i 2f, tijadiazolini 8a i 8e i tiazolidin-4-oni 9a i 10a. Pritom su koeficijenti selektivnosti u antikancerskom dejstvu prema malignim ćelijama u odnosu na normalne humane PBMC, kako na nestimulisane tako i na mitogenom stimulisane, bili daleko veći od vrednosti 2,5 što ova jedinjenja svrstava u potencijalne kandidate za in vivo ispitivanja. Sumporni derivati bili su daleko aktivniji od kiseoničnih. Najaktivniji derivati indukovali su apoptozu posredstvom kaspaza-3, -8 i -9 i inhibirali angiogezu in vitro zbog čega se smatra da poseduju značajan antikancerski potencijal. Searching for biologically active compounds, within this doctoral dissertation fifty new steroidal hydrazone derivatives, of which 11 thiosemicarbazones, 11 thiadiazolines, 12 thiazolidin-4-ones, 11 semicarbazones and 5 carbazate esters, were synthesized starting with progesterone and 3-oxo-α,β-unsaturated androstene steroids, and fully characterized. For the first time, detailed stereochemistry analyses of steroidal hydrazones in the C- 3/17 positions of androstene derivatives, or C-3/20 positions of progesterone derivatives was done. Structure and stereochemistry were confirmed by the results of X-ray analyses for thiadiazoline 7a, the first characterized steroid compound that contains sixmembered carbon ring condensed with the spiro-thiadiazoline ring, and thiazolidinone 9b-E, the first steroidal derivative with known configuration of double bond in C-3 position of the hydrazono-thiazolidin-4-one fragment. Synthesised compounds manifested the best cytotoxicity towards HeLa cervix adenocarcinoma cells, and K562 cells of chronic myeloide leukemia, the best activity being showed by thiosemicarbazones 2a, 2b, 2c and 2f, thiadiazolines 8a and 8e, and thiazolidin-4-ones 9a and 10a. All of these compounds exhibited considerably higher intensities of cytotoxic action against malignant cells when compared with normal human PBMC, both resting and mitogen-stimulated, with coefficient of selectivity higher than 2.5, which makes these compounds potential candidates for in vivo experiments. Sulfur derivatives were much more active than oxygen derivatives. The most active derivatives induced apoptosis mediated by caspase-3, -8 and -9, and they inhibited angiogenesis in vitro, because of what they are considered to have significant anticancer potential.

Eleven new steroidal mono- and bis(semicarbazones)2a–e, 4d and 3a–e have been prepared starting from various 3-oxo-α,β-unsaturated steroids. Mono-semicarbazones 2a–e were further subjected to ethyl chloroacetate in boiling absolute ethanol but, instead of expected intramolecular cyclocondensation reaction products, the new carbazate esters 5a-e were obtained. The structures of all synthesized compounds and identification of each E/Z isomer were deduced by elemental analysis, HRMS, NMR, and IR spectroscopy. Preliminary screening for the cytotoxic activity in vitro of the new compounds has been conducted against three cancer cell lines, K562, Jurkat and HeLa cells. HeLa cells were the most sensitive while K562 cells were the least sensitive to the cytotoxic action of the novel steroid derivatives. Compounds 2e, 3c and 5e were found to have the best but still moderate cytotoxic effects. All tested compounds showed very weak antimicrobial activities. These results demonstrate that the replacement of thioxo group with carbonyl group in steroidal hydrazone derivatives resulted in decrease in their biological activity. Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3083] This is peer-reviewed version of the following article: Živković, M. B.; Novaković, I. T.; Matić, I. Z.; Sladić, D. M.; Krstić, N. M. Synthesis and Preliminary Screening for the Biological Activity of Some Steroidal Δ4-Unsaturated Semicarbazone Derivatives. Steroids 2019, 148, 36–46. [https://doi.org/10.1016/j.steroids.2019.04.010]