28336-29-0

Over the last decades, much effort has been devoted to the design of the “ideal” library for screening, the most promising strategies being those which draw inspiration from biogenic compounds, as the aim is to add biological relevance to such libraries. On the other hand, there is a growing understanding of the role that molecular complexity plays in the discovery of new bioactive small molecules. Nevertheless, the introduction of molecular complexity must be balanced with synthetic accessibility. In this work, we show that both concepts can be efficiently merged—in a minimalist way—by using very simple guidelines during the design process along with the application of multicomponent reactions as key steps in the synthetic process. Natural phenanthrenoids, a class of plant aromatic metabolites, served as inspiration for the synthesis of a library in which complexity-enhancing features were introduced in few steps using multicomponent reactions. These resulting chemical entities were not only more complex than the parent natural products, but also interrogated an alternative region of the chemical space, which led to an outstanding hit rate in an antiproliferative assay: four out of twenty-six compounds showed in vitro activity, one of them being more potent than the clinically useful drug 5-fluorouracil.

In this study, eighteen novel steroidal-furoxan derivatives with 3-glycosyl or 3-methoxy moiety (12a-c, 13a-c, 17a-c, 26a-c, 27a-c and 28a-c) were synthesized and their anti-proliferative activity was evaluated against eight drug-sensitive and three drug-resistant cancer cell lines HeLa, A2780, LNCaP, PC-3, MDA-MB-231, MCF-7, SW480, A549, MCF-7/ADR, A2780/CDDP and A2780/T. Most of them displayed significant anti-cancer potency in vitro with IC50 values at the nanomole level. Among them, 3-methoxy steroidal-furoxan hybrids expressed much better activity than that of 3-glycosyl substitute ones, while estrane and 5α-H-androstane scaffold were slightly more favorable to the improvement of anti-proliferative activity. Especially, compounds 27c and 28b showed the strongest cytotoxicity with IC50 values of 0.0007–0.034 and 0.0011–0.008 μM, respectively in five drug-sensitive cancer cell lines. Furthermore, 3-glycoconjugates 13a, 13c, 17b and 3-methoxy compounds 27a, 27c, 28b displayed lower toxicity in nontumorigenesis cells HOSEC and expressed a good selectivity against malignant cells in vitro. Preliminary study of pharmacology showed that the introduction of glucose at 3-position in steroidal core seems unable to use glucose transporters to improve the selectivity against proliferation of malignant cells, while the NO-releasing capacity might explain the potent anti-neoplastic activity of these compounds. And compound 28b could induce the apoptosis and hardly affected the cell cycle of A2780. Then, the further study of these steroidal-furoxan hybrids merits to explore and develop a desirable anti-cancer candidate.

Series of estrone based analogs were synthetically investigated at positions C-9, C-11, C-16, and C-17 positions, to be biologically evaluated via assessment of cell proliferation, cytotoxicity, and estrogenic/anti-estrogenic activity. LA-7 and LA-10 revealed their potential to exhibit inhibitory estrogenic profile. This was further validated by Estrogen Receptor-α (ER-α) and Estrogen Receptor-β (ER-β) competitive binding assays to reveal the high selective affinity of LA-7 towards ER-α at 5.49 μM, while LA-10 did not show any binding affinity towards neither ER-α nor ER-β; suggesting another mechanism for inhibition. This was validated by in silico molecular docking simulations of LA-7 to reveal the optimum binding affinity of LA-7 towards ER-α.

The invention discloses a method for preparing a 19-Norandrost-5(10)-ene-3,17-dione compound. The method comprises the steps of by taking estrone as an ingredient, firstly sequentially performing etherification reaction, ketal protection reaction and birch reduction reaction to obtain a birch reduction product; then by taking lower fatty acid as a catalyst, performing selective hydrolysis reaction on the birch reduction product to produce the 19-Norandrost-5(10)-ene-3,17-dione compound. According to the method, the hydrolysis technology of the birch reduction product containing 17-bit ketal protecting group is optimized and improved, and the single 19-Norandrost-5(10)-ene-3,17-dione with high yield and high selectivity can be obtained through selective hydrolysis reaction by taking binary fatty acid as an acid catalyst for the first time; in addition, the fact that the 17-bit ketal protecting derivatives of the single 19-Norandrost-5(10)-ene-3,17-dione compound can be obtained by taking lower unitary fatty acid as a catalyst is found for the first time.

A fast, general, low-temperature rearrangement of ortho-iodobenzyl esters, triggered by lithium-iodine exchange, leads to isobenzofurans which are intercepted in situ by inter and intramolecular Diels-Alder (IMDA) reactions to produce a variety of carbocycles including natural lignans and steroids.

New derivatives of 17-β-estradiol with N-butyl, N-methyl alkylamide side chains of three different lengths at position 15 have been synthesized from estrone.Compounds 5 and 6 having a shorter alkylamide chain were obtained in eleven steps by introduction

Dimethyl carbonate (as well as diethyl, diallyl, dibenzyl carbonate and ethane-1,2-diyl carbonate) in the presence of potassium carbonate and 18-crown-6 (or Aliqual 336) is a versatile, cheap, and safer reagent for the methylation of a variety of organic substrates.

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