Prototyping kinase inhibitor-cytotoxin anticancer mutual prodrugs activated by tumour hypoxia: A chemical proof of concept study

被引：8

作者：

Sansom, Geraud N. ^{[1
,2
,3
]}

Kirk, Nicholas S. ^{[1
,2
,3
]}

Guise, Christopher P. ^{[4
,5
]}

Anderson, Robert F. ^{[4
,5
]}

Smaill, Jeff B. ^{[4
,5
]}

Patterson, Adam, V ^{[4
,5
]}

Kelso, Michael J. ^{[1
,2
,3
]}

机构：

[1] Univ Wollongong, Mol Horizons, Wollongong, NSW 2522, Australia

[2] Univ Wollongong, Sch Chem & Mol Biosci, Wollongong, NSW 2522, Australia

[3] Illawarra Hlth & Med Res Inst, Wollongong, NSW 2522, Australia

[4] Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc, Res Ctr, Private Bag 92019, Auckland 1142, New Zealand

[5] Univ Auckland, Maurice Wilkins Ctr Mol Biodiscovery, Private Bag 92019, Auckland 1142, New Zealand

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 10期

基金：

英国医学研究理事会;

关键词：

Hypoxia; Mutual prodrug; Anticancer; Bioreductive activation; Sunitinib; Semaxinib; Floxuridine; 4-Aminoaniline mustard; NITRO REDUCTION; PHASE-II; DESIGN; SU5416; INDOLIN-2-ONES; DERIVATIVES; DELIVERY;

D O I：

10.1016/j.bmcl.2019.03.015

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Amide- and ester-linked kinase inhibitor-cytotoxin conjugates were rationally designed and synthesised as prototype hypoxia-activated anticancer mutual prodrugs. Chemical reduction of an aryl nitro trigger moiety was shown to initiate a spontaneous cyclisation/fragmentation reaction that simultaneously released the kinase inhibitor semaxanib (SU5416) and the amine- or alcohol-linked cytotoxin from the prodrugs. Preliminary cell testing and reduction potential measurements support optimisation of the compounds towards tumour-selective mutual prodrugs.

引用

页码：1215 / 1219

页数：5

共 30 条

[1] RELATIONSHIPS BETWEEN STRUCTURE AND KINETICS OF CYCLIZATION OF 2-AMINOARYL AMIDES - POTENTIAL PRODRUGS OF CYCLIZATION-ACTIVATED AROMATIC MUSTARDS [J].