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  3. Computational and synthetic studies towards improving rescinnamine as an inducer of MSH2-dependent apoptosis in cancer treatment

Computational and synthetic studies towards improving rescinnamine as an inducer of MSH2-dependent apoptosis in cancer treatment

  • Mol Cancer Biol. 2013;1(1):44.
ElShimaa M N AbdelHafez 1,  Andrew Diamanduros 2,  Lacramioara Negureanu 3,  Yan Luy 3,  J Hayley Bean 2,  Katherine Zielke 2,  Brittany Crowe 2,  Aksana Vasilyeva 4,  Jill E Clodfelter 5,  Omar M Aly 6,  Gamal El-Din A A Abuo-Rahma 6,  Karin D Scarpinato 2,  Freddie R Salsbury Jr 3,  S Bruce King 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Wake Forest University, Winston-Salem, NC.
  • 2 Department of Biology, Georgia Southern University, Statesboro, GA.
  • 3 Department of Physics, Wake Forest University, Winston-Salem, NC.
  • 4 Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC; now: St. Jude Hospital, Memphis, TN.
  • 5 Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC.
  • 6 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia , Egypt.
PMID: 25485184
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.

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