ABSTRACT
A novel series of trifluoromethyl indole derivatives have been designed, synthesized and evaluated for anti-HIV-1 activities in MT-2 cells. The hydrophobic constant, acute toxicity, carcinogenicity and mutagenicity were predicted. Trifluoromethyl indoles 10i and 10k showed extremely promising activities against WT HIV-1 with IC50 values at the low nanomolar level, similar to efavirenz, better than nevirapine, and also possessed higher potency towards the drug-resistant mutant strain Y181C than nevirapine. Preliminary SAR and docking studies of detailed binding mode provided some insights for discovery of more potent NNRTIs.
Subject(s)
Drug Design , Drug Resistance, Viral/drug effects , HIV-1/drug effects , Indoles/chemical synthesis , Indoles/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Aldehydes/chemistry , Alkynes , Benzoxazines/chemistry , Benzoxazines/pharmacology , Carcinogens/toxicity , Catalysis , Cell Line , Cyclopropanes , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/metabolism , Humans , Indoles/chemistry , Ligands , Models, Molecular , Mutagens/toxicity , Mutant Proteins/chemistry , Mutant Proteins/metabolism , Reverse Transcriptase Inhibitors/chemistryABSTRACT
Compound 1 ((-)-gossypol) has been long known as a chemical anticancer agent. With its low water solubility and toxicity, it is not widely used as a commercial drug. To overcome these disadvantages, several novel derivatives of gossypol were designed, synthesized, and analyzed. One of the derivatives, compound 7 (6-aminopenicillanic acid sodium-gossypolone), was identified with great water solubility and anticancer property, suggested by inducing a dramatically decrease in Bcl-2 and Bcl-xL protein expression level found in vitro and growth inhibition of murine colon tumor in vivo. Furthermore, it was also recognized with less toxicity than compound 1 in vivo and significantly increased chemotherapeutic sensitivity against colon cancer in combination with traditional chemotherapeutic agent 5-fluorouracil. Therefore, it is concluded that compound 7 is superior to parent compound 1, and further preclinical studies of compound 7 is necessary for colon cancer therapy.
