title: Novel 9'-substituted-noscapines: synthesis with Suzuki cross-coupling, structure elucidation and biological evaluation.
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.
authors: Department of Woman's and Child's Health, Laboratory of Oncohematology, University of Padova, Via Giustiniani 2, Padova 35128, Italy.
authors: Elena
authors: E
authors: Porcù
authors: Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, Hungary.
authors: Attila
authors: A
authors: Sipos
authors: Department of Woman's and Child's Health, Laboratory of Oncohematology, University of Padova, Via Giustiniani 2, Padova 35128, Italy.
authors: Giuseppe
authors: G
authors: Basso
authors: 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.
authors: Ernest
authors: E
authors: Hamel
authors: 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.
authors: Ruoli
authors: R
authors: Bai
authors: Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria.
authors: Verena
authors: V
authors: Stempfer
authors: Department of Physical Chemistry, University of Debrecen, Hungary.
authors: Antal
authors: A
authors: Udvardy
authors: Department of Physical Chemistry, University of Debrecen, Hungary; Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, Hungary.
authors: Attila Cs
authors: AC
authors: Bényei
authors: Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria.
authors: Helmut
authors: H
authors: Schmidhammer
authors: Department of Organic Chemistry, University of Debrecen, Hungary.
authors: Sándor
authors: S
authors: Antus
authors: 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.
authors: Giampietro
authors: G
authors: Viola
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D062105:Molecular Docking Simulation; D009665:Noscapine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D051017:Apoptosis Regulatory Proteins; D009665:Noscapine
keywords: Antimicrotubule agents; Apoptosis; Cell cycle arrest; Noscapine; Suzuki reaction