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Structure−Function Correlation of Chloroquine and Analogues as Transgene Expression Enhancers in Nonviral Gene Delivery

Cheng, Jianjun and Zeidan, Ryan and Mishra, Swaroop and Liu, Aijie and Pun, Suzie H. and Kulkarni, Rajan P. and Jensen, Gregory S. and Bellocq, Nathalie C. and Davis, Mark E. (2006) Structure−Function Correlation of Chloroquine and Analogues as Transgene Expression Enhancers in Nonviral Gene Delivery. Journal of Medicinal Chemistry, 49 (22). pp. 6522-6531. ISSN 0022-2623. doi:10.1021/jm060736sD.

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To understand how chloroquine (CQ) enhances transgene expression in polycation-based, nonviral gene delivery systems, a number of CQ analogues with variations in the aliphatic amino side chain or in the aromatic ring are synthesized and investigated. Our studies indicate that the aliphatic amino moiety of CQ is essential to provide increased gene expression. Further, the enhancements are more dramatically affected by changes to the aromatic ring and are positively correlated to the strength of intercalation between DNA and the CQ analogues. Quinacrine (QC), a CQ analogue with a fused acridinyl structure that can strongly intercalate DNA, enhances transfection similarly to CQ at a concentration 10 times lower, while N^4-(4-pyridinyl)-N^1,N^1-diethyl-1,4-pentanediamine (CP), a CQ analogue that has a weakly intercalating pyridinyl ring, shows no effect on gene expression. Subtle change on the 7-substituent of the chloroquine aromatic structure can also greatly affect the ability of the CQ analogues to enhance transgene expression. Transfection in the presence of N^4-(7-trifluoromethyl-4-quinolinyl)-N^1,N^1-diethyl-1,4-pentanediamin e (CQ7a) shows expression efficiency 10 times higher than in the presence of CQ at same concentration, while transfection in the presence of N^4-(4-quinolinyl)-N^1,N^1-diethyl-1,4-pentanediamine (CQ7b) does not reveal any enhancing effects on expression. Through a number of comparative studies with CQ and its analogues, we conclude that there are at least three mechanistic features of CQ that lead to the enhancement in gene expression:  (i) pH buffering in endocytic vesicles, (ii) displacement of polycations from the nucleic acids in polyplexes, and (iii) alteration of the biophysical properties of the released nucleic acid.

Item Type:Article
Related URLs:
URLURL TypeDescription Information
Mishra, Swaroop0000-0002-2665-5385
Pun, Suzie H.0000-0003-1443-4996
Davis, Mark E.0000-0001-8294-1477
Additional Information:© 2006 American Chemical Society. Received 19 June 2006. Published online 7 October 2006. Published in print 1 November 2006. We thank Insert Therapeutics for financial support.
Funding AgencyGrant Number
Insert Therapeutics, Inc.UNSPECIFIED
Issue or Number:22
Record Number:CaltechAUTHORS:20170517-070821385
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Official Citation:Structure−Function Correlation of Chloroquine and Analogues as Transgene Expression Enhancers in Nonviral Gene Delivery Jianjun Cheng, Ryan Zeidan, Swaroop Mishra, Aijie Liu, Suzie H. Pun, Rajan P. Kulkarni, Gregory S. Jensen, Nathalie C. Bellocq, and Mark E. Davis Journal of Medicinal Chemistry 2006 49 (22), 6522-6531 DOI: 10.1021/jm060736s
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:77521
Deposited By: Ruth Sustaita
Deposited On:17 May 2017 16:08
Last Modified:15 Nov 2021 17:31

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