title: Computational and synthetic studies towards improving rescinnamine as an inducer of MSH2-dependent apoptosis in cancer treatment.
abstract: We, and others, have previously shown that mismatch repair proteins, in addition to their repair function, contribute to cell death initiation. In response to some drugs, this cell death activity is independent of the repair function of the proteins. Rescinnamine, a derivative of the indole alkaloid reserpine, a drug used to treat hypertension several decades ago, was shown to target the cell death-initiating activity of mismatch repair proteins. When used in animals, the hypotensive action of this drug prevents applying appropriate concentrations for statistically significant tumor reduction. Using a combination of computational modeling, chemical synthesis and cell assays, we determine how rescinnamine can be structurally modified and what effect these modifications have on cell survival. These results inform further computational modeling to suggest new synthetic lead molecules to move toward further biological testing.
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC.
authors.forename: ElShimaa M N
authors.initials: EM
authors.lastname: AbdelHafez
authors.affiliation: Department of Biology, Georgia Southern University, Statesboro, GA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Diamanduros
authors.affiliation: Department of Physics, Wake Forest University, Winston-Salem, NC.
authors.forename: Lacramioara
authors.initials: L
authors.lastname: Negureanu
authors.affiliation: Department of Physics, Wake Forest University, Winston-Salem, NC.
authors.forename: Yan
authors.initials: Y
authors.lastname: Luy
authors.affiliation: Department of Biology, Georgia Southern University, Statesboro, GA.
authors.forename: J Hayley
authors.initials: JH
authors.lastname: Bean
authors.affiliation: Department of Biology, Georgia Southern University, Statesboro, GA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Zielke
authors.affiliation: Department of Biology, Georgia Southern University, Statesboro, GA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Crowe
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC; now: St. Jude Hospital, Memphis, TN.
authors.forename: Aksana
authors.initials: A
authors.lastname: Vasilyeva
authors.affiliation: Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Clodfelter
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia , Egypt.
authors.forename: Omar M
authors.initials: OM
authors.lastname: Aly
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia , Egypt.
authors.forename: Gamal El-Din A A
authors.initials: GE
authors.lastname: Abuo-Rahma
authors.affiliation: Department of Biology, Georgia Southern University, Statesboro, GA.
authors.forename: Karin D
authors.initials: KD
authors.lastname: Scarpinato
authors.affiliation: Department of Physics, Wake Forest University, Winston-Salem, NC.
authors.forename: Freddie R
authors.initials: FR
authors.lastname: Salsbury
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC.
authors.forename: S Bruce
authors.initials: SB
authors.lastname: King