Tyrosinase-mediated cytotoxicity of 4-substituted phenols: Use of QSAR to forecast reactivities of thiols towards the derived ortho-quinones

被引:28
作者
Cooksey, CJ
Land, EJ
Rushton, FAP
Ramsden, CA
Riley, PA
机构
[1] CHRISTIE HOSP NHS TRUST, PATERSON INST CANC RES, CRC DEPT BIOPHYS CHEM, MANCHESTER M20 9BX, LANCS, ENGLAND
[2] UNIV LONDON UNIV COLL, DEPT CHEM, LONDON WC1H 0AJ, ENGLAND
[3] UNIV KEELE, DEPT CHEM, KEELE ST5 5BG, STAFFS, ENGLAND
[4] UNIV COLL & MIDDLESEX SCH MED, DEPT MOL PATHOL, LONDON W1P 6DB, ENGLAND
来源
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS | 1996年 / 15卷 / 06期
关键词
tyrosinase-mediated cytotoxicity; 4-substituted phenols; o-quinones; thiols; malignant melanoma; Hammett constants; QSAR;
D O I
10.1002/qsar.19960150606
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Certain 4-substituted phenols can behave as tyrosine analogues and undergo tyrosinase-catalysed oxidation to cytotoxic o-quinones which react with crucial cellular thiols. Such phenols are potential melanogenesis-specific pro-drugs for the chemotherapy of malignant melanoma. Previously (Cooksey et al. (1995) Anti-Cancer Drug Design, 10, 119), by pulse radiolysis under oxidative conditions of the corresponding stable catechols in the presence and absence of thiols, we showed that the glutathione and cysteine reactivities of ten 4-substituted o-quinones correlated well with the Hammett sigma(p) constants of the corresponding substituents. Starting from the corresponding catechols, one of which has not previously been described, we have now investigated six further 4-substituted o-quinones including two with substituent sigma(p) values higher than those previously studied. Extrapolation of the earlier quantitative structure - activity relationships (QSAR) correctly predicted the high reactivities of these two o-quinones, with respective substituents OCF3 and CH2NH3+, towards thiols. The data for all sixteen 4-substituted o-quinones, and for o-benzoquinone itself, have been combined to provide updated, statistically significant Hammett and Swain-Lupton correlations, including multivariate regressions using the data for both thiols. These relationships show that in reacting the substituted o-quinones with thiols, the rate constants increase with the electron withdrawing capacities of the substituent groups, this being principally due to the resonance effect, with a smaller but significant contribution attributable to the field effect. Such QSAR may facilitate the design of improved melanogenesis - targeted anti-melanoma pro-drugs.
引用
收藏
页码:498 / 503
页数:6
相关论文
共 25 条
[1]  
Adams G.E., 1965, PULSE RADIOLYSIS, P117
[2]   REACTION OF AZIDE RADICALS WITH AROMATIC-COMPOUNDS - AZIDE AS A SELECTIVE OXIDANT [J].
ALFASSI, ZB ;
SCHULER, RH .
JOURNAL OF PHYSICAL CHEMISTRY, 1985, 89 (15) :3359-3363
[3]   INTRAARTERIAL 4-HYDROXYANISOLE CHEMOTHERAPY FOR LOCALLY RECURRENT MALIGNANT-MELANOMA - A REAPPRAISAL [J].
BELCHER, HJCR ;
NIZAM, M ;
ONEILL, TJ .
BRITISH JOURNAL OF PLASTIC SURGERY, 1992, 45 (03) :208-210
[4]  
Bensasson R.V., 1993, EXCITED STATES FREE
[5]  
BUTLER J, 1989, RADIAT PHYS CHEM, V34, P633
[6]   THE AZIDE RADICAL AND ITS REACTION WITH TRYPTOPHAN AND TYROSINE [J].
BUTLER, J ;
LAND, EJ ;
SWALLOW, AJ ;
PRUTZ, W .
RADIATION PHYSICS AND CHEMISTRY, 1984, 23 (1-2) :265-270
[7]   A TEMPLATE EFFECT IN THE SYNTHESIS OF DIBENZO-14-CROWN-4 DERIVATIVES [J].
CHEN, CS ;
WANG, SJ ;
WU, SC .
JOURNAL OF HETEROCYCLIC CHEMISTRY, 1983, 20 (03) :795-798
[8]  
Cooksey C J, 1987, Free Radic Res Commun, V4, P131, DOI 10.3109/10715768709088098
[9]   REACTIVITY OF ORTHOQUINONES INVOLVED IN TYROSINASE-DEPENDENT CYTOTOXICITY - DIFFERENCES BETWEEN ALKYLTHIO-SUBSTITUENTS AND ALKOXY-SUBSTITUENTS [J].
COOKSEY, CJ ;
JIMBOW, K ;
LAND, EJ ;
RILEY, PA .
MELANOMA RESEARCH, 1992, 2 (5-6) :283-293
[10]  
COOKSEY CJ, 1995, ANTI-CANCER DRUG DES, V10, P119