Elena Porcù1, Attila Sipos2, Giuseppe Basso1, Ernest Hamel3, Ruoli Bai3, Verena Stempfer4, Antal Udvardy5, Attila Cs Bényei6, Helmut Schmidhammer4, Sándor Antus7, Giampietro Viola8. 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.
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.
Tubulin is a major molecular target for antin class="Disease">cancer drugs. The dynamic process of microtubule assembly anpan>d disassembly canpan> be blocked by various agents that bind to distinct sites onpan> tubulin, usually its β-subunit. Amonpan>g the anpan>timitotic agents that perturb microtubule dynamics, pan> class="Chemical">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 humancancer 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: K Ye; Y Ke; N Keshava; J Shanks; J A Kapp; R R Tekmal; J Petros; H C Joshi Journal: Proc Natl Acad Sci U S A Date: 1998-02-17 Impact factor: 11.205
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