Structure-activity relationships for mitomycin C and mitomycin A analogues

Kenneth R. Kunz, Bhashyam S. Iyengar, Robert T. Dorr, Robert T Dorr, David S Alberts

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

A set of 30 mitomycin C and mitomycin A analogues, including five new compounds, was screened against three different solid human tumor cell lines using the MTT tetrazolium dye assay. A statistically significant correlation among antitumor activity, quinone reduction potential (E1/2), and the logarithm of the partition coefficient (log P) was obtained, with the most easily reduced and the most lipophilic compounds being the most potent. When these analogues were separated into mitomycin C and mitomycin A subsets, the former gave a correlation only with E1/2, whereas the latter (which differ little in their E1/2 values) gave a correlation only with log P. These correlations are in contrast to those made in the P388 leukemia assay in mice wherein the most active mitomycin C and mitomycin A analogues were the most hydrophilic ones. When the same compounds were tested against P388 leukemia cells in the MTT assay, the results were the same as those of the solid tumor assays. Thus, the substantial differences in relative potencies of mitomycins are related not to the kind of tumor cell, but to the type of assay performed, cell culture versus whole animal. No correlation was found between antitumor potency in the cell culture systems and calculated relative DNA binding strengths, probably because the limiting factors in antitumor potency of mitomycins appear to be tumor cell uptake (log P) and/or bioreductive activation (E1/2).

Original languageEnglish (US)
Pages (from-to)2281-2286
Number of pages6
JournalJournal of Medicinal Chemistry
Volume34
Issue number7
StatePublished - 1991

Fingerprint

Mitomycins
Mitomycin
Structure-Activity Relationship
Leukemia P388
Assays
Tumors
Cell Culture Techniques
Cells
Neoplasms
Cell culture
Tumor Cell Line
Coloring Agents
DNA
Animals
Chemical activation
mitomycin A

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Structure-activity relationships for mitomycin C and mitomycin A analogues. / Kunz, Kenneth R.; Iyengar, Bhashyam S.; Dorr, Robert T.; Dorr, Robert T; Alberts, David S.

In: Journal of Medicinal Chemistry, Vol. 34, No. 7, 1991, p. 2281-2286.

Research output: Contribution to journalArticle

Kunz, Kenneth R. ; Iyengar, Bhashyam S. ; Dorr, Robert T. ; Dorr, Robert T ; Alberts, David S. / Structure-activity relationships for mitomycin C and mitomycin A analogues. In: Journal of Medicinal Chemistry. 1991 ; Vol. 34, No. 7. pp. 2281-2286.
@article{5b159fcede5343e897a9ef430863f952,
title = "Structure-activity relationships for mitomycin C and mitomycin A analogues",
abstract = "A set of 30 mitomycin C and mitomycin A analogues, including five new compounds, was screened against three different solid human tumor cell lines using the MTT tetrazolium dye assay. A statistically significant correlation among antitumor activity, quinone reduction potential (E1/2), and the logarithm of the partition coefficient (log P) was obtained, with the most easily reduced and the most lipophilic compounds being the most potent. When these analogues were separated into mitomycin C and mitomycin A subsets, the former gave a correlation only with E1/2, whereas the latter (which differ little in their E1/2 values) gave a correlation only with log P. These correlations are in contrast to those made in the P388 leukemia assay in mice wherein the most active mitomycin C and mitomycin A analogues were the most hydrophilic ones. When the same compounds were tested against P388 leukemia cells in the MTT assay, the results were the same as those of the solid tumor assays. Thus, the substantial differences in relative potencies of mitomycins are related not to the kind of tumor cell, but to the type of assay performed, cell culture versus whole animal. No correlation was found between antitumor potency in the cell culture systems and calculated relative DNA binding strengths, probably because the limiting factors in antitumor potency of mitomycins appear to be tumor cell uptake (log P) and/or bioreductive activation (E1/2).",
author = "Kunz, {Kenneth R.} and Iyengar, {Bhashyam S.} and Dorr, {Robert T.} and Dorr, {Robert T} and Alberts, {David S}",
year = "1991",
language = "English (US)",
volume = "34",
pages = "2281--2286",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "7",

}

TY - JOUR

T1 - Structure-activity relationships for mitomycin C and mitomycin A analogues

AU - Kunz, Kenneth R.

AU - Iyengar, Bhashyam S.

AU - Dorr, Robert T.

AU - Dorr, Robert T

AU - Alberts, David S

PY - 1991

Y1 - 1991

N2 - A set of 30 mitomycin C and mitomycin A analogues, including five new compounds, was screened against three different solid human tumor cell lines using the MTT tetrazolium dye assay. A statistically significant correlation among antitumor activity, quinone reduction potential (E1/2), and the logarithm of the partition coefficient (log P) was obtained, with the most easily reduced and the most lipophilic compounds being the most potent. When these analogues were separated into mitomycin C and mitomycin A subsets, the former gave a correlation only with E1/2, whereas the latter (which differ little in their E1/2 values) gave a correlation only with log P. These correlations are in contrast to those made in the P388 leukemia assay in mice wherein the most active mitomycin C and mitomycin A analogues were the most hydrophilic ones. When the same compounds were tested against P388 leukemia cells in the MTT assay, the results were the same as those of the solid tumor assays. Thus, the substantial differences in relative potencies of mitomycins are related not to the kind of tumor cell, but to the type of assay performed, cell culture versus whole animal. No correlation was found between antitumor potency in the cell culture systems and calculated relative DNA binding strengths, probably because the limiting factors in antitumor potency of mitomycins appear to be tumor cell uptake (log P) and/or bioreductive activation (E1/2).

AB - A set of 30 mitomycin C and mitomycin A analogues, including five new compounds, was screened against three different solid human tumor cell lines using the MTT tetrazolium dye assay. A statistically significant correlation among antitumor activity, quinone reduction potential (E1/2), and the logarithm of the partition coefficient (log P) was obtained, with the most easily reduced and the most lipophilic compounds being the most potent. When these analogues were separated into mitomycin C and mitomycin A subsets, the former gave a correlation only with E1/2, whereas the latter (which differ little in their E1/2 values) gave a correlation only with log P. These correlations are in contrast to those made in the P388 leukemia assay in mice wherein the most active mitomycin C and mitomycin A analogues were the most hydrophilic ones. When the same compounds were tested against P388 leukemia cells in the MTT assay, the results were the same as those of the solid tumor assays. Thus, the substantial differences in relative potencies of mitomycins are related not to the kind of tumor cell, but to the type of assay performed, cell culture versus whole animal. No correlation was found between antitumor potency in the cell culture systems and calculated relative DNA binding strengths, probably because the limiting factors in antitumor potency of mitomycins appear to be tumor cell uptake (log P) and/or bioreductive activation (E1/2).

UR - http://www.scopus.com/inward/record.url?scp=0025826451&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025826451&partnerID=8YFLogxK

M3 - Article

VL - 34

SP - 2281

EP - 2286

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 7

ER -