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

Ahmed Kamal; T Srinivasa Reddy; Sowjanya Polepalli; Suresh Paidakula; Vunnam Srinivasulu; V Ganga Reddy; Nishant Jain; Nagula Shankaraiah

doi:10.1016/j.bmcl.2014.05.096

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. Epub 2014 Jun 6.

Authors

Ahmed Kamal¹, T Srinivasa Reddy², Sowjanya Polepalli³, Suresh Paidakula⁴, Vunnam Srinivasulu⁴, V Ganga Reddy⁴, Nishant Jain³, Nagula Shankaraiah⁵

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HeLa Cells
Heterocyclic Compounds, 4 or More Rings / chemical synthesis
Heterocyclic Compounds, 4 or More Rings / chemistry
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Humans
MCF-7 Cells
Molecular Structure
Phenanthrolines / chemical synthesis
Phenanthrolines / chemistry
Phenanthrolines / pharmacology*
Polymerization / drug effects
Structure-Activity Relationship
Tubulin / metabolism*
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry
Tubulin Modulators / pharmacology*

Substances

13-(2-fluoro-5-methoxyphenyl)-10,13-dihydrofuro(3,4-b)pyrido(3,2-f)(1,7)phenanthrolin-12(9H)-one
13-(3,4-difluorophenyl)-10,13-dihydrofuro(3,4-b)pyrido(3,2-f)(1,7)phenanthrolin-12-(9H)-one
Antineoplastic Agents
Heterocyclic Compounds, 4 or More Rings
Phenanthrolines
Tubulin
Tubulin Modulators