Camptothecin analogs with enhanced activity against human breastcancer cells. I. Correlation of potency with lipophilicity and persistence inthe cleavage complex

DJ Adams, Mateus Webba da Silva, G Kohlhagen, Y Pommier, OM Colvin, G Manikumar, MC Wani

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The effect of 7-alkyl substitutions on growthinhibition in seven Camptothecin (CPT) ring systemswith various groups at the ten position was evaluated inthree human breast cancer cell lines that model (1)hormone-sensitive (MCF-7/wt), (2) hormone insensitive(MDA-MB-231), or (3) alkylator-resistant (MCF-7/4-hc) forms of disease. To assess the impact of persistenceof cleavage complexes on antiproliferative activity, apost-exposure recovery period in drug-free medium wasincorporated into the growth inhibition assay. Thismodification produced on average a twofold reductionin the growth inhibition endpoint (the IC50), suggestinga greater apoptotic response. The results further revealeda three log range in potency from a mean IC50 of2 nM (7-butyl-10,11-methylenedioxy-CPT) to 2.5 lM(7-bromomethyl-10-hydryoxy-CPT). Increasing 7-alkylchain length in six of the ten-substituted CPTs enhancedpotency, which was directly correlated with persistenceof topoisomerase I-induced DNA cleavage complexes in10-hydroxy, 10-methoxy, and 10,11-methylenedioxysubstituted CPTs. Modeling of the binding mode of 7-butyl-10-amino-CPT revealed a direct hydrogen bondcontact for the 10-amino to the side chain of Glu-356 ofCore Subdomain I of top1 in addition to known contactsfound for other camptothecins. More important,residues 350–356 and 425–431 of Core Subdomain I mayprovide induced fit stabilization to the lipophilic alkylmoiety at the seven position.
LanguageEnglish
JournalCancer Chemotherapy Pharmacology
Volume57
DOIs
Publication statusPublished - 20 Aug 2005

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irinotecan
Camptothecin
Human Activities
Inhibitory Concentration 50
Hormones
Type I DNA Topoisomerase
DNA Cleavage
Alkylating Agents
Growth
Hydrogen
Breast Neoplasms
Cell Line
Pharmaceutical Preparations

Cite this

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title = "Camptothecin analogs with enhanced activity against human breastcancer cells. I. Correlation of potency with lipophilicity and persistence inthe cleavage complex",
abstract = "The effect of 7-alkyl substitutions on growthinhibition in seven Camptothecin (CPT) ring systemswith various groups at the ten position was evaluated inthree human breast cancer cell lines that model (1)hormone-sensitive (MCF-7/wt), (2) hormone insensitive(MDA-MB-231), or (3) alkylator-resistant (MCF-7/4-hc) forms of disease. To assess the impact of persistenceof cleavage complexes on antiproliferative activity, apost-exposure recovery period in drug-free medium wasincorporated into the growth inhibition assay. Thismodification produced on average a twofold reductionin the growth inhibition endpoint (the IC50), suggestinga greater apoptotic response. The results further revealeda three log range in potency from a mean IC50 of2 nM (7-butyl-10,11-methylenedioxy-CPT) to 2.5 lM(7-bromomethyl-10-hydryoxy-CPT). Increasing 7-alkylchain length in six of the ten-substituted CPTs enhancedpotency, which was directly correlated with persistenceof topoisomerase I-induced DNA cleavage complexes in10-hydroxy, 10-methoxy, and 10,11-methylenedioxysubstituted CPTs. Modeling of the binding mode of 7-butyl-10-amino-CPT revealed a direct hydrogen bondcontact for the 10-amino to the side chain of Glu-356 ofCore Subdomain I of top1 in addition to known contactsfound for other camptothecins. More important,residues 350–356 and 425–431 of Core Subdomain I mayprovide induced fit stabilization to the lipophilic alkylmoiety at the seven position.",
author = "DJ Adams and {Webba da Silva}, Mateus and G Kohlhagen and Y Pommier and OM Colvin and G Manikumar and MC Wani",
year = "2005",
month = "8",
day = "20",
doi = "10.1007/s00280-005-0007-6",
language = "English",
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Camptothecin analogs with enhanced activity against human breastcancer cells. I. Correlation of potency with lipophilicity and persistence inthe cleavage complex. / Adams, DJ; Webba da Silva, Mateus; Kohlhagen, G; Pommier, Y; Colvin, OM; Manikumar, G; Wani, MC.

In: Cancer Chemotherapy Pharmacology, Vol. 57, 20.08.2005.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Camptothecin analogs with enhanced activity against human breastcancer cells. I. Correlation of potency with lipophilicity and persistence inthe cleavage complex

AU - Adams, DJ

AU - Webba da Silva, Mateus

AU - Kohlhagen, G

AU - Pommier, Y

AU - Colvin, OM

AU - Manikumar, G

AU - Wani, MC

PY - 2005/8/20

Y1 - 2005/8/20

N2 - The effect of 7-alkyl substitutions on growthinhibition in seven Camptothecin (CPT) ring systemswith various groups at the ten position was evaluated inthree human breast cancer cell lines that model (1)hormone-sensitive (MCF-7/wt), (2) hormone insensitive(MDA-MB-231), or (3) alkylator-resistant (MCF-7/4-hc) forms of disease. To assess the impact of persistenceof cleavage complexes on antiproliferative activity, apost-exposure recovery period in drug-free medium wasincorporated into the growth inhibition assay. Thismodification produced on average a twofold reductionin the growth inhibition endpoint (the IC50), suggestinga greater apoptotic response. The results further revealeda three log range in potency from a mean IC50 of2 nM (7-butyl-10,11-methylenedioxy-CPT) to 2.5 lM(7-bromomethyl-10-hydryoxy-CPT). Increasing 7-alkylchain length in six of the ten-substituted CPTs enhancedpotency, which was directly correlated with persistenceof topoisomerase I-induced DNA cleavage complexes in10-hydroxy, 10-methoxy, and 10,11-methylenedioxysubstituted CPTs. Modeling of the binding mode of 7-butyl-10-amino-CPT revealed a direct hydrogen bondcontact for the 10-amino to the side chain of Glu-356 ofCore Subdomain I of top1 in addition to known contactsfound for other camptothecins. More important,residues 350–356 and 425–431 of Core Subdomain I mayprovide induced fit stabilization to the lipophilic alkylmoiety at the seven position.

AB - The effect of 7-alkyl substitutions on growthinhibition in seven Camptothecin (CPT) ring systemswith various groups at the ten position was evaluated inthree human breast cancer cell lines that model (1)hormone-sensitive (MCF-7/wt), (2) hormone insensitive(MDA-MB-231), or (3) alkylator-resistant (MCF-7/4-hc) forms of disease. To assess the impact of persistenceof cleavage complexes on antiproliferative activity, apost-exposure recovery period in drug-free medium wasincorporated into the growth inhibition assay. Thismodification produced on average a twofold reductionin the growth inhibition endpoint (the IC50), suggestinga greater apoptotic response. The results further revealeda three log range in potency from a mean IC50 of2 nM (7-butyl-10,11-methylenedioxy-CPT) to 2.5 lM(7-bromomethyl-10-hydryoxy-CPT). Increasing 7-alkylchain length in six of the ten-substituted CPTs enhancedpotency, which was directly correlated with persistenceof topoisomerase I-induced DNA cleavage complexes in10-hydroxy, 10-methoxy, and 10,11-methylenedioxysubstituted CPTs. Modeling of the binding mode of 7-butyl-10-amino-CPT revealed a direct hydrogen bondcontact for the 10-amino to the side chain of Glu-356 ofCore Subdomain I of top1 in addition to known contactsfound for other camptothecins. More important,residues 350–356 and 425–431 of Core Subdomain I mayprovide induced fit stabilization to the lipophilic alkylmoiety at the seven position.

U2 - 10.1007/s00280-005-0007-6

DO - 10.1007/s00280-005-0007-6

M3 - Article

VL - 57

JO - Cancer Chemotherapy Pharmacology

T2 - Cancer Chemotherapy Pharmacology

JF - Cancer Chemotherapy Pharmacology

SN - 0344-5704

ER -