Synthesis and evaluation of Strychnos alkaloids as MDR reversal agents for cancer cell eradication

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 3; pp. 1148 - 1155
• Main Authors: Munagala, Surendrachary, Sirasani, Gopal, Kokkonda, Praveen, Phadke, Manali, Krynetskaia, Natalia, Lu, Peihua, Sharom, Frances J., Chaudhury, Sidhartha, Abdulhameed, Mohamed Diwan M., Tawa, Gregory, Wallqvist, Anders, Martinez, Rogelio, Childers, Wayne, Abou-Gharbia, Magid, Krynetskiy, Evgeny, Andrade, Rodrigo B.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.02.2014; Elsevier
• Subjects: ABCB1; Adenosine Triphosphatases - metabolism; Alkaloids - chemical synthesis; Alkaloids - chemistry; Alkaloids - pharmacology; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - chemistry; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biochemistry & Molecular Biology; Cell Line, Tumor - drug effects; Chemistry; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Chemistry, Organic; Docking; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Heterocyclic Compounds, 4 or More Rings - chemical synthesis; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Indole Alkaloids - chemical synthesis; Indole Alkaloids - chemistry; Indole Alkaloids - pharmacology; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Life Sciences & Biomedicine; Molecular Docking Simulation; Multidrug resistance; P-glycoprotein; Pharmacology & Pharmacy; Physical Sciences; Protein Conformation; Resensitization; Science & Technology; Strychnos; Strychnos - chemistry; Strychnos alkaloids; Total synthesis; Tubocurarine - analogs & derivatives; Tubocurarine - chemical synthesis; Tubocurarine - chemistry; Tubocurarine - pharmacology; Verapamil - pharmacology; P-glycoprotein; ABCB1; Multidrug resistance; Docking; Strychnos alkaloids; Total synthesis; Resensitization; NATURAL-PRODUCTS; GLIDE; ACCURATE DOCKING; (-)-TUBIFOLIDINE; LEUKEMIA; MULTIDRUG-RESISTANCE; CYTOTOXICITY
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.12.022

Natural products represent the fourth generation of multidrug resistance (MDR) reversal agents that resensitize MDR cancer cells overexpressing P-glycoprotein (Pgp) to cytotoxic agents. We have developed an effective synthetic route to prepare various Strychnos alkaloids and their derivatives. Molecular modeling of these alkaloids docked to a homology model of Pgp was employed to optimize ligand–protein interactions and design analogues with increased affinity to Pgp. Moreover, the compounds were evaluated for their (1) binding affinity to Pgp by fluorescence quenching, and (2) MDR reversal activity using a panel of in vitro and cell-based assays and compared to verapamil, a known inhibitor of Pgp activity. Compound 7 revealed the highest affinity to Pgp of all Strychnos congeners (Kd=4.4μM), the strongest inhibition of Pgp ATPase activity, and the strongest MDR reversal effect in two Pgp-expressing cell lines. Altogether, our findings suggest the clinical potential of these synthesized compounds as viable Pgp modulators justifies further investigation.