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

Srinivasa Rao Ramisetti, Manoj K. Pandey, Sang Lee, Deepkamal Karelia, Satya Narayan, Shantu Amin, Arun Sharma

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1919-1930
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume143
DOIs
StatePublished - Jan 1 2018

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Melanoma
Assays
Cells
Derivatives
Cell death
Tumor Cell Line
Tumors
Colon
Breast
Cell Death
Genes
Western Blotting
Cell Line
thiobarbituric acid
Therapeutics
barbituric acid
trienyl

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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title = "Design and synthesis of novel thiobarbituric acid derivatives targeting both wild-type and BRAF-mutated melanoma cells",
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.",
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Design and synthesis of novel thiobarbituric acid derivatives targeting both wild-type and BRAF-mutated melanoma cells. / Ramisetti, Srinivasa Rao; Pandey, Manoj K.; Lee, Sang; Karelia, Deepkamal; Narayan, Satya; Amin, Shantu; Sharma, Arun.

In: European Journal of Medicinal Chemistry, Vol. 143, 01.01.2018, p. 1919-1930.

Research output: Contribution to journalArticle

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AU - Pandey, Manoj K.

AU - Lee, Sang

AU - Karelia, Deepkamal

AU - Narayan, Satya

AU - Amin, Shantu

AU - Sharma, Arun

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