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Novel derivatives of Mycosidine (3,5-substituted thiazolidine-2,4-diones) are synthesized by Knoevenagel condensation and reactions of thiazolidines with chloroformates or halo-acetic acid esters. Furthermore, 5-Arylidene-2,4-thiazolidinediones and their 2-thioxo analogs containing halogen and hydroxy groups or di(benzyloxy) substituents in 5-benzylidene moiety are tested for antifungal activity in vitro. Some of the synthesized compounds exhibit high antifungal activity, both fungistatic and fungicidal, and lead to morphological changes in the Candida yeast cell wall. Based on the use of limited proteomic screening and toxicity analysis in mutants, we show that Mycosidine activity is associated with glucose transport. This suggests that this first-in-class antifungal drug has a novel mechanism of action that deserves further study.

Indole-3-carbinol (I3C), a natural autolysis product of a gluccosinolate present in Brassica vegetables such as broccoli and cabbage, has anti-proliferative and anti-estrogenic activities in human breast cancer cells. A new and significantly more potent I3C analogue, 1-benzyl-I3C was synthesized, and in comparison to I3C, this novel derivative displayed an approximate 1000-fold enhanced potency in suppressing the growth of both estrogen responsive (MCF-7) and estrogen independent (MDA-MB-231) human breast cancer cells (I3C IC50 of 52 μM, and 1-benzyl-I3C IC50 of 0.05 μM). At significantly lower concentrations, 1-benzyl-I3C induced a robust G1 cell cycle arrest and elicited the key I3C-specific effects on expression and activity of G1 acting cell cycle genes including the disruption of endogenous interactions of the Sp1 transcription factor with the CDK6 promoter. Furthermore, in estrogen responsive MCF-7 cells, with enhanced potency 1-benzyl-I3C down regulated production of estrogen receptor-alpha protein, acts with tamoxifen to arrest breast cancer cell growth more effectively than either compound alone, and inhibited the in vivo growth of human breast cancer cell-derived tumor xenografts in athymic mice. Our results implicate 1-benzyl-I3C as a novel, potent inhibitor of human breast cancer proliferation and estrogen responsiveness that could potentially be developed into a promising therapeutic agent for the treatment of indole-sensitive cancers.

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Tris(1 alkylindol 3 yl)methanes were obtained and oxidized into tris(1 alkylindol 3 yl)methylium salts. The resulting salts are more toxic to cultured tumor cells than to non tumor ones. The cytotoxicity of tris(1 alkylindol 3 yl)methylium salts depends on the length of the substituent at the N atom of the heterocycle, increasing from an N unsubstituted derivative toward N butyl and N pentyl derivatives. A further increase in the length of the N alkyl substituent lowers the cytotoxicity. The cytotoxicity of tris(1 alkylindol 3 yl)methylium salts for tumor cells correlates with their antibacterial and antifungal activity. Tris(1 alkylindol 3 yl)methylium salts produced a cytocide effect on Gram positive microorganisms and the most active compounds, on Gram negative microorganisms as well. Similar patterns of the struc ture-activity relationship of N alkylated tris(indol 3 yl)methylium derivatives, which was ob served for various lines of tumor cells, bacteria, and fungi, suggest the general character of the mechanisms of the death of prokaryotic and eukaryotic cells induced by these compounds.