2. Academic Validation
  3. Synthesis and biological evaluation of 4-aza-2,3-dihydropyridophenanthrolines as tubulin polymerization inhibitors

Synthesis and biological evaluation of 4-aza-2,3-dihydropyridophenanthrolines as tubulin polymerization inhibitors

  • Bioorg Med Chem Lett. 2014 Aug 1;24(15):3356-60. doi: 10.1016/j.bmcl.2014.05.096.
Ahmed Kamal 1,  T Srinivasa Reddy 2,  Sowjanya Polepalli 3,  Suresh Paidakula 4,  Vunnam Srinivasulu 4,  V Ganga Reddy 4,  Nishant Jain 3,  Nagula Shankaraiah 5
Affiliations

Affiliations

  • 1 Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: ahmedkamal@iict.res.in.
  • 2 Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India; IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
  • 3 Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
  • 4 Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
  • 5 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
PMID: 24953821 DOI: 10.1016/j.bmcl.2014.05.096
Abstract

A series of novel 4-aza-2,3-dihydropyridophenanthrolines 12(a-t) were synthesized by a one-step three component condensation of 1,10-phenanthroline amine, tetronic acid and various aromatic aldehydes. These were evaluated for their antiproliferative activity against three human Cancer cell lines (MIAPACA, MCF-7 and HeLa) using SRB assay. Majority of the tested compounds exhibited significant Anticancer activity on these cell lines and interestingly compounds 12h and 12i were more potent than etoposide and podophyllotoxin against all three tested Cancer cell lines with GI50 values in the range of 0.01-0.5 μM. Furthermore, these compounds showed significant inhibition of tubulin polymerization which is comparable to that of podophyllotoxin and disrupted microtubule network by accumulating tubulin in the soluble fraction. The flow cytometry analysis confirmed that the synthesized compounds led to cell cycle arrest at the G2/M phase. Moreover, the structure activity relationship studies in this series are also discussed.

Keywords

1,10-Phenanthroline; 4-Azapodophyllotoxin; Cytotoxicity; Multicomponent reaction; Tubulin polymerization.

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