ABSTRACT
The synthesis, SAR, and preclinical evaluation of 17-cyanated 2-substituted estra-1,3,5(10)-trienes as anticancer agents are discussed. 2-Methoxy-17beta-cyanomethylestra-1,3,5(10)-trien-3-ol ( 14), but not the related 2-ethyl derivative 7, and the related 3- O-sulfamates 8 and 15 display potent antiproliferative effects (MCF-7 GI 50 300, 60 and 70 nM, respectively) against human cancer cells in vitro. Investigation of the SAR reveals that a sterically unhindered hydrogen bond acceptor attached to C-17 is most likely key to the enhanced activity. Compound 8 displayed significant in vitro antiangiogenic activity, and its ability to act as a microtubule disruptor was confirmed. Inhibitory activity of the sulfamate derivatives against steroid sulfatase and carbonic anhydrase II (hCAII) was also observed, and the interaction between 15 and hCAII was investigated by protein crystallography. The potential of these multimechanism anticancer agents was confirmed in vivo, with promising activity observed for both 14 and 15 in an athymic nude mouse MDA-MB-231 human breast cancer xenograft model.
Subject(s)
Antineoplastic Agents/chemical synthesis , Estradiol/analogs & derivatives , Estrenes/chemical synthesis , Models, Molecular , Nitriles/chemical synthesis , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Estradiol/chemical synthesis , Estradiol/chemistry , Estradiol/pharmacology , Estrenes/chemistry , Estrenes/pharmacology , Female , Humans , Mice , Mice, Nude , Molecular Conformation , Neoplasm Transplantation , Nitriles/chemistry , Nitriles/pharmacology , Stereoisomerism , Steryl-Sulfatase/antagonists & inhibitors , Structure-Activity Relationship , Transplantation, Heterologous , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
A series of combretastatins substituted with epoxides, amides and small alkyl groups has been synthesised and evaluated for cytotoxicity and their ability to inhibit the assembly of tubulin. The methyl and ethyl substituted phenols 36, 44 have shown potent antimitotic effects whilst exhibiting reduced cytotoxicity.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Bibenzyls/chemical synthesis , Bibenzyls/pharmacology , Stilbenes/chemical synthesis , Stilbenes/pharmacology , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Antineoplastic Agents/chemistry , Bibenzyls/chemistry , Cell Cycle/drug effects , Cell Survival/drug effects , Epoxy Compounds/chemical synthesis , Epoxy Compounds/chemistry , Epoxy Compounds/pharmacology , Formazans/chemistry , Humans , Inhibitory Concentration 50 , K562 Cells , Magnetic Resonance Spectroscopy , Molecular Structure , Spectrophotometry, Ultraviolet , Stilbenes/chemistry , Tetrazolium Salts/chemistry , Tubulin/metabolism , Tubulin ModulatorsABSTRACT
A series of combretastatins possessing both a trimethoxy unit and other substituents on ring A has been synthesised and tested for cytotoxicity and their ability to interact with the protein tubulin. All previous studies have indicated that the trimethoxy unit is essential for interaction with tubulin. The studies herein show that molecules possessing functionalities other than trimethoxy can also interact with tubulin. Importantly a trimethyl substituted agent 52a has shown reduced cytotoxicity, but increased potency in its ability to inhibit the assembly of tubulin.
