Antitumor structure-activity relationships. Nitrosoureas vs. L-1210 leukemia

Hansch, Corwin; Leo, Alessandro De; Schmidt, Charles L.; Jow, P. Y. C.; Montgomery, John A.

doi:10.1021/jm00184a007

Cited by 45 publications

(19 citation statements)

References 3 publications

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“…The observed biological activity data used for the QSAR analyses are the values of log(1/ C ) obtained from Hansch et al19. C is the molar concentration (mol/kg) of CCNU derivatives producing a reduction of 1000‐fold of leukemia cells in mice.…”

Section: Resultsmentioning

confidence: 99%

“…A small number of investigations using QSAR to study DNA alkylating agents relevant to nitrosoureas have been reported. Hansh19 established a QSAR model for 90 nitrosoureas acting against L‐1210 leukemia in mice and showed that neutral nitrosoureas with octanol/water partition coefficients in the range −1.5 to −2.5 might have better therapeutic indices. Panasci et al20 performed a structure‐activity analysis of the chemical and biological parameters of CENUs in mice.…”

Section: Introductionmentioning

confidence: 99%

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Relationship between the molecular structure and the anticancer activity of N‐(2‐chloroethyl)‐N′‐cyclohexyl‐N‐nitrosoureas: A theoretical investigation

Cao

Zhao

Jin

et al. 2011

Int J of Quantum Chemistry

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N-(2-chloroethyl)-N 0 -cyclohexyl-N-nitrosoureas (CCNU) is an important alkylating agent used in the clinical treatment of cancer. The quantitative structureactivity relationship (QSAR) of CCNU derivatives was investigated using the density functional theory (DFT)-based descriptors and the n-octanol/water partition coefficient (milogP). Geometry optimization was performed using the DFT/B3LYP method in conjunction with the 6-311þG(d,p) basis set. Experimental data of anticancer activity, log(1/C), were used for the QSAR analysis. By stepwise multiple regressions, four optimum descriptors, (milog P)2 , E 1 , E Z/E and B O1ACl8 were found for constructing the QSAR models. Two satisfied models were obtained by multiple linear regressions with the values of R 2 higher than 0.9. The (milog P) 2 descriptor has the highest correlation to the anticancer activity, indicating that similar improvements to hydrophilicity and lipophilicity are necessary for enhancing anticancer activity. The energy barriers for the decomposition of CCNU derivatives via a retro-ene reaction (E 1 ) and for the transformation from Z-tautomers to E-tautomers (E Z/E ) are also considerable descriptors in the QSAR models. The anticancer activity is increased with the decrease of E 1 and the increase of E Z/E . The B O1ACl8 descriptor, which requires the inclusion of the other three descriptors in the models, has positive correlation with the anticancer activity of CCNU derivatives. The results indicate that the introduction of the descriptors of activation energies (E 1 and E Z/E ) is a significant contribution to the methodology of QSAR investigations, because the dynamic descriptors may be more correlated with the biological activity of drugs and toxicants than the static descriptors. Our models shed light on the structure-activity relationship of CCNU derivatives and may be useful in the development of more effective and less toxic nitrosoureas as anticancer agents.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relationship between the molecular structure and the anticancer activity of N‐(2‐chloroethyl)‐N′‐cyclohexyl‐N‐nitrosoureas: A theoretical investigation

Cao

Zhao

Jin

et al. 2011

Int J of Quantum Chemistry

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“…This was originally thought to be due to their increased water solubility caused by the glucose moiety [5] and produced a spate of substances, such as GANU [6], HeCNU and analogues [7,8]. After further experiments the conclusion was reached that water solubility was not correlated with reduced myelotoxicity, [9][10][11].…”

Section: Introductionmentioning

confidence: 82%

Anti-tumour, toxicological and pharmacokinetic properties of a novel taurine-based nitrosourea (TCNU)

Hartley-Asp¹,

Christensson²,

Gunnarsson³

et al. 1988

Invest New Drugs

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A novel nitrosourea, 1-(2-chloroethyl)-3-[2-(dimethylaminosulfonyl) ethyl]-1-nitrosourea (TCNU) tauromustine, has been investigated in a broad anti-tumour screen and, in depth toxicology and initial pharmacokinetics carried out. TCNU and its two metabolites were found to exhibit equal or better oral efficacy than that of BCNU, CCNU, MeCCNU or chorozotocin against L1210 leukemia, Walker mammary carcinoma, Lewis Lung, Harding Passey melanoma and colon carcinoma C26. The toxicological profile of TCNU after acute and 3 months treatment was similar in mice and rats to that of CCNU, with the exception that, TCNU did not cause the chronic liver disturbances found for CCNU. In dogs treated for 6 weeks with TCNU leucopenia and thrombocytopenia were the major side effects. Parent TCNU was found in all dogs. The absorption was fast, the maximum level being reach after 25 mins and the mean absorption time was 22 mins. The mean half life was 16.1 mins after intravenous and 17.4 after oral administration. The combination of these factors make TCNU an interesting clinical candidate.

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“…The ideal log P range was found to be -0.20 to +1.34 against this cancer cell line. A similar study of 90 nitrosoureas against the L1210 leukemia in mice revealed that nitrosoureas with log P values of -1.5 to -2.5 would have the more favorable therapeutic indices [427]. The anticancer activity of 17 nitrosoureas against intraperitoneal-inoculated L1210 was directly correlated with the alkylating activity which increased with decreasing hydrophobicity [428].…”

Section: Predictive Correlations Of Lipophilicity Parameters With In mentioning

confidence: 97%

“…Since the hydrophobic term often has an overwhelming effect on the rate constant k 1 , it is not unreasonable to emphasize the lipophilicity of drugs in QSAR studies [421]. QSARs of anticancer agents have been correlated with log P values [424,425,427]. A group of 14 nitrosoureas, with log P values ranging from 4.5 to -2.2, were tested for their ability to delay the growth of Lewis lung carcinoma in mice [425].…”

Section: Predictive Correlations Of Lipophilicity Parameters With In mentioning

confidence: 99%

Critical appraisals of approaches for predictive designs in anticancer drugs

Gnewuch

Sosnovsky

2002

Cellular and Molecular Life Sciences (CMLS)

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The present review provides a critical appraisal of the most important areas in cancer drug research and, ultimately, in clinical oncology and therapy, with emphasis on the elucidation of possible predictive designs for the development of new anticancer drugs. These assessments encompass the well-established anticancer drugs and congeners which have been employed over the years in clinical therapy, and the more recent exploratory agents still requiring further rigorous scrutiny in the clinical environment. These areas mainly include the bioreversible redox carriers, the boron neutron capture compounds, some new mitosis-interactive agents, cell cycle modifiers, biological-response mpdifiers, oncogene inhibitors, drug-antibody conjugates, cancer cell suppression and destruction agents, antiangiogenesis and antimetastasis agents, apoptosis-promoting agents, and gene therapy and vaccines.

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Antitumor structure-activity relationships. Nitrosoureas vs. L-1210 leukemia

Cited by 45 publications

References 3 publications

Relationship between the molecular structure and the anticancer activity of N‐(2‐chloroethyl)‐N′‐cyclohexyl‐N‐nitrosoureas: A theoretical investigation

Relationship between the molecular structure and the anticancer activity of N‐(2‐chloroethyl)‐N′‐cyclohexyl‐N‐nitrosoureas: A theoretical investigation

Anti-tumour, toxicological and pharmacokinetic properties of a novel taurine-based nitrosourea (TCNU)

Critical appraisals of approaches for predictive designs in anticancer drugs

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