In vitro and in vivo anticancer activity of novel synthetic makaluvamine analogues.

Abstract

PURPOSE:

The present study was designed to determine biological structure-activity relationships for four newly synthesized analogues of natural compounds (makaluvamines). The compounds, 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ); 7-(phenethylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (PEA-TPQ); 7-(3,4-methylenedioxyphenethylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (MPA-TPQ); and 7-(3,4-dimethoxyphenethylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (DPA-TPQ), were synthesized and purified, and their chemical structures were elucidated on the basis of physicochemical constants and nuclear magnetic resonance spectra.

EXPERIMENTAL DESIGN:

The structure-activity relationship of the compounds was initially evaluated by comparing their in vitro cytotoxicity against 14 human cell lines. Detailed in vitro and in vivo studies were then done in MCF-7 and MDA-MB-468 breast cancer cell lines.

RESULTS:

The in vitro cytotoxicity was compound, dose, and cell line dependent. Whereas all of the compounds exerted some activity, FBA-TPQ was the most potent inducer of apoptosis and the most effective inhibitor of cell growth and proliferation, with half maximal inhibitory concentration values for most cell lines in the range of 0.097 to 2.297 mumol/L. In MCF-7 cells, FBA-TPQ exposure led to an increase in p53/p-p53, Bax, ATM/p-ATM, p-chk1 and p-chk2, and p-H2AX; and cleavage of poly(ADP)ribose polymerase, caspase-3, caspase-8, and caspase-9. It also decreased the levels of MDM2, E2F1, Bcl-2, chk1/2, and proteins associated with cell proliferation [cyclin-dependent kinase (Cdk)2, Cdk4, Cdk6, cyclin D1, etc.]. Moreover, FBA-TPQ inhibited the growth of breast cancer xenograft tumors in nude mice in a dose-dependent manner. Western blot analysis ofthe xenograft tumors indicated that similar changes in protein expression also occur in vivo.

CONCLUSION:

Our preclinical data indicate that FBA-TPQ is a potential therapeutic agent for breast cancer, providing a basis for the development of the compound as a novel anticancer agent.

• Authors: Wei Wang, Elizabeth R Rayburn, Sadanandan E Velu, Dwayaja H Nadkarni, Srinivasan Murugesan, Ruiwen Zhang
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 10 Pg. 3511-8 (May 15 2009) ISSN: 1078-0432 [Print] United States
• PMID: 19451594 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Cell Cycle Proteins
• Pyrroles
• Quinolones
• makaluvamine A

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Blotting, Western
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Female
• Humans
• Mammary Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Molecular Structure
• Pyrroles (chemical synthesis, chemistry, pharmacology)
• Quinolones (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays