2. Academic Validation
  3. Design and synthesis of novel thiobarbituric acid derivatives targeting both wild-type and BRAF-mutated melanoma cells

Design and synthesis of novel thiobarbituric acid derivatives targeting both wild-type and BRAF-mutated melanoma cells

  • Eur J Med Chem. 2018 Jan 1:143:1919-1930. doi: 10.1016/j.ejmech.2017.11.006.
Srinivasa Rao Ramisetti 1,  Manoj K Pandey 1,  Sang Y Lee 2,  Deepkamal Karelia 1,  Satya Narayan 3,  Shantu Amin 1,  Arun K Sharma 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
  • 2 Department of Neurosurgery, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
  • 3 Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610, USA.
  • 4 Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Electronic address: aks14@psu.edu.
PMID: 29133035 DOI: 10.1016/j.ejmech.2017.11.006
Abstract

A series of novel thio- and seleno-barbituric acid derivatives were synthesized by varying the substituents at N1 and N3 (ethyl, methyl, allyl, and phenyl), and C5 tethered with dienyl and trienyl moieties attached to substituents such as phenyl, 2-furanyl, 2-thiophenyl, 1-naphthyl, and 3-pyridyl. The cytotoxic potential of these derivatives was evaluated by using MTT assay against melanoma cell lines expressing either wild-type (CHL-1) or mutant (UACC 903) BRaf gene. Among all, 2b and 8b were identified as the most potent compounds. Both 2b and 8b inhibited viability of various melanoma cells and induced cell death as evidenced by Live and Dead assay. Western blot analysis showed that they induce PARP cleavage and inhibit anti-apoptotic Bcl-2, Bcl-xL and Survivin in a dose-dependent manner within 24 h of the treatment. Novel thiobarbituric acid analogs also inhibited viability of various Other solid tumor cell lines, such as pancreatic, breast, and colon. Overall, 2b, 2d, and 8b emerged as the most effective compounds and make good leads for the development of future therapeutic agents.

Keywords

Anti-cancer; Apoptosis; Melanoma; Selenobarbiturates; Thiobarbiturates.

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