Preclinical evaluation of anticancer efficacy and pharmacological properties of FBA-TPQ, a novel synthetic makaluvamine analog.

Abstract

We have recently designed and synthesized a novel iminoquinone anticancer agent, 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ) and initiated its preclinical development. Herein we investigated its efficacy, safety, and pharmacokinetics in in vitro and in vivo models of human pancreatic cancer. Our results demonstrated that FBA-TPQ inhibited pancreatic cancer cell growth, induced apoptosis, and caused cell cycle arrest in vitro. It inhibited the growth of xenograft tumors with minimal host toxicity. To facilitate future preclinical and clinical development of the agent, we also developed and validated a Rapid Resolution Liquid Chromatography (RRLC) method for quantitative analysis of FBA-TPQ in plasma and tissue samples. The method was found to be precise, accurate, and specific. Using this method, we carried out in vitro and in vivo evaluations of the pharmacological properties of FBA-TPQ, including stability in plasma, plasma protein binding, metabolism by S9 enzymes, plasma pharmacokinetics, and tissue distribution. Our results indicate that FBA-TPQ is a potential therapeutic agent for pancreatic cancer, providing a basis for future preclinical and clinical development.

• Authors: Xiangrong Zhang, Hongxia Xu, Xu Zhang, Sukesh Voruganti, Srinivasan Murugesan, Dwayaja H Nadkarni, Sadanandan E Velu, Ming-Hai Wang, Wei Wang, Ruiwen Zhang
• Journal: Marine drugs (Mar Drugs) Vol. 10 Issue 5 Pg. 1138-1155 (May 2012) ISSN: 1660-3397 [Electronic] Switzerland
• PMID: 22822362 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo(4,3,2-de)quinolin-8(1H)-one
• Antineoplastic Agents
• Pyrroles
• Quinolones

Topics

• Animals
• Antineoplastic Agents (adverse effects, pharmacokinetics, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Evaluation, Preclinical (methods)
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Protein Binding (drug effects)
• Pyrroles (adverse effects, pharmacokinetics, pharmacology)
• Quinolones (adverse effects, pharmacokinetics, pharmacology)
• Tissue Distribution (drug effects)
• Xenograft Model Antitumor Assays (methods)