piperidines and fumagillin

Natural products are an abundant source of anti cancer agents. They act as cytotoxic drugs, and inhibitors of apoptosis, transcription, cell proliferation and angiogenesis. While pathways targeted by natural products have been well studied, there is paucity of information about the in vivo molecular target/s of these compounds. This review summarizes some of the natural compounds for which the molecular targets, mechanism of action and structural basis of specificity have been well documented. These examples illustrate that 'off target' binding can be explained on the basis of diversity inherent to biomolecular interactions. There is enough evidence to suggest that natural compounds are potent and versatile warheads that can be optimized for a multi targeted therapeutic intervention in cancer.

Topics: Antineoplastic Agents; Benzamides; Biological Products; Cyclohexanes; Epoxy Compounds; Fatty Acids, Unsaturated; Flavonoids; Humans; Imatinib Mesylate; Macrolides; Neoplasms; Piperazines; Piperidines; Proteins; Pyrimidines; Sesquiterpenes

Type 2 diabetes (T2DM) is a progressive insulin secretory defect accompanied by resistance to insulin, and thereby making glycemic control a major concern in the treatment of these patients. Oral drug administration, though a popular option for its non-invasiveness, suffer from poor bioavailability. It could be related to the efflux transport of intestinal P-glycoprotein (Pgp). In the present study, we explored the binding interactions of antidiabetic drugs i.e., sulfonylurea drugs (glimepiride, glipizide, glyburide) and rapid acting insulin secretagogues viz., nateglinide, repaglinide and rosiglitazone; and Pgp inhibitors i.e., Generation I (verapamil and tamoxifen), III (tetradrine and tariquidar), and natural inhibitors (fumagillin and piperine) in mouse Pgp model. Our results revealed that fumagillin piperine and verapamil possess maximum interaction energies with Pgp compared to antidiabetic drugs. These observations elucidate the role of fumagillin and piperine as potential natural compounds which could intervene in the efflux action of Pgp in extruding the antidiabetic drugs and may have implications for increasing efficacy of oral antidiabetic therapy.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Transport, Active; Cyclohexanes; Fatty Acids, Unsaturated; Hypoglycemic Agents; Intestinal Mucosa; Mice; Molecular Docking Simulation; Piperidines; Polyunsaturated Alkamides; Protein Binding; Sesquiterpenes; Tamoxifen; Verapamil