Design, synthesis and biological evaluation of novel homocamptothecin analogues as potent antitumor agents

Lei Wang; Shao Xie; Longjun Ma; Yi Chen; Wei Lu

doi:10.1016/j.bmc.2015.03.031

Design, synthesis and biological evaluation of novel homocamptothecin analogues as potent antitumor agents

Bioorg Med Chem. 2015 May 1;23(9):1950-62. doi: 10.1016/j.bmc.2015.03.031. Epub 2015 Mar 18.

Authors

Lei Wang¹, Shao Xie², Longjun Ma¹, Yi Chen³, Wei Lu⁴

Affiliations

¹ School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
² Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
³ Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: [email protected].
⁴ School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China. Electronic address: [email protected].

PMID: 25835359
DOI: 10.1016/j.bmc.2015.03.031

Abstract

Fifteen novel homocamptothecin derivatives with α-OMe substituted E-rings were designed and synthesized. All of the derivatives exhibited similar or superior cytotoxicities compared with that of SN-38, and they inhibited Topo I activity in a cell-free assay in a manner similar to that of SN-38, confirming that they represent a new class of Topo I inhibitors. Notably, the water soluble compound 36o (1.2 mg/mL) exhibited increased lactone stability, and at 0.5 mg/kg and 3.0 mg/kg, it demonstrated significant antitumor activity in mice bearing a xenograft model using human colon cancer cell line HT-29. On the basis of these positive results, further development of 36o-related compounds as potential anticancer clinical trial candidates is definitely warranted.

Keywords: Anticancer drug; Homocamptothecin; Lactone stability; Water solubility.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Camptothecin / analogs & derivatives*
Camptothecin / chemistry
Camptothecin / pharmacology
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
HT29 Cells
Humans
Mice
Molecular Structure
Neoplasms, Experimental / drug therapy*
Neoplasms, Experimental / pathology
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
homocamptothecin
Camptothecin