2. Academic Validation
  3. Novel 9'-substituted-noscapines: synthesis with Suzuki cross-coupling, structure elucidation and biological evaluation

Novel 9'-substituted-noscapines: synthesis with Suzuki cross-coupling, structure elucidation and biological evaluation

  • Eur J Med Chem. 2014 Sep 12:84:476-90. doi: 10.1016/j.ejmech.2014.07.050.
Elena Porcù 1,  Attila Sipos 2,  Giuseppe Basso 1,  Ernest Hamel 3,  Ruoli Bai 3,  Verena Stempfer 4,  Antal Udvardy 5,  Attila Cs Bényei 6,  Helmut Schmidhammer 4,  Sándor Antus 7,  Giampietro Viola 8
Affiliations

Affiliations

  • 1 Department of Woman's and Child's Health, Laboratory of Oncohematology, University of Padova, Via Giustiniani 2, Padova 35128, Italy.
  • 2 Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, Hungary.
  • 3 Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
  • 4 Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria.
  • 5 Department of Physical Chemistry, University of Debrecen, Hungary.
  • 6 Department of Physical Chemistry, University of Debrecen, Hungary; Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, Hungary.
  • 7 Department of Organic Chemistry, University of Debrecen, Hungary.
  • 8 Department of Woman's and Child's Health, Laboratory of Oncohematology, University of Padova, Via Giustiniani 2, Padova 35128, Italy. Electronic address: Giampietro.viola.1@unipd.it.
PMID: 25050880 DOI: 10.1016/j.ejmech.2014.07.050
Abstract

Tubulin is a major molecular target for Anticancer drugs. The dynamic process of microtubule assembly and disassembly can be blocked by various agents that bind to distinct sites on tubulin, usually its β-subunit. Among the antimitotic agents that perturb microtubule dynamics, noscapinoids represent an emerging class of agents. In particular, 9'-bromonoscapine (EM011) has been identified as a potent noscapine analog. Here we present high yielding, efficient synthetic methods based on Suzuki coupling of 9'-alkyl and 9'-arylnoscapines and an evaluation of their antiproliferative properties. Our results showed that 9'-alkyl and 9'-aryl derivatives inhibit proliferation of human Cancer cells. The most active compounds were the 9'-methyl and the 9'-phenyl derivatives, which showed similar cytotoxic potency in comparison to the 9'-brominated derivative. Interestingly these newly synthesized derivatives did not induce cell death in normal human lymphocytes, suggesting that the compounds may be selective against Cancer cells. All of these derivatives, except 9'-(2-methoxyphenyl)-noscapine, efficiently induced a cell cycle arrest in the G2/M phase of the cell cycle in HeLa and Jurkat cells. Furthermore, we showed that the most active compounds in HeLa cells induced Apoptosis following the mitochondrial pathway with the activation of both caspase-9 and Caspase-3. In addition, these compounds significantly reduced the expression of the anti-apoptotic proteins Mcl-1 and Bcl-2.

Keywords

Antimicrotubule agents; Apoptosis; Cell cycle arrest; Noscapine; Suzuki reaction.

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