title: Synthesis and evaluation of Strychnos alkaloids as MDR reversal agents for cancer cell eradication.
abstract: 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.
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
authors.forename: Surendrachary
authors.initials: S
authors.lastname: Munagala
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
authors.forename: Gopal
authors.initials: G
authors.lastname: Sirasani
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
authors.forename: Praveen
authors.initials: P
authors.lastname: Kokkonda
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19122, United States.
authors.forename: Manali
authors.initials: M
authors.lastname: Phadke
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19122, United States.
authors.forename: Natalia
authors.initials: N
authors.lastname: Krynetskaia
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Peihua
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Sharom
authors.affiliation: Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, United States.
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Chaudhury
authors.affiliation: Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, United States.
authors.forename: Mohamed Diwan M
authors.initials: MD
authors.lastname: Abdulhameed
authors.affiliation: Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Tawa
authors.affiliation: Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, United States.
authors.forename: Anders
authors.initials: A
authors.lastname: Wallqvist
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19122, United States.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Martinez
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19122, United States.
authors.forename: Wayne
authors.initials: W
authors.lastname: Childers
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19122, United States.
authors.forename: Magid
authors.initials: M
authors.lastname: Abou-Gharbia
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19122, United States.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Krynetskiy
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, PA 19122, United States. Electronic address: randrade@temple.edu.
authors.forename: Rodrigo B
authors.initials: RB
authors.lastname: Andrade
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D026121:Indole Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D031451:Strychnos / Q000737:chemistry*; D014403:Tubocurarine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: C412590:19,20-dihydroakuammicine; C000592632:3,4,5-trimethoxybenzyl leuconicine B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D006576:Heterocyclic Compounds, 4 or More Rings; D026121:Indole Alkaloids; D007211:Indoles; C541002:norfluorocurarine; D014700:Verapamil; D000251:Adenosine Triphosphatases; C434103:akuammicine; D014403:Tubocurarine
keywords: ABCB1; Docking; Multidrug resistance; P-glycoprotein; Resensitization; Strychnos alkaloids; Total synthesis