STRUCTURAL STUDIES ON BIOACTIVE COMPOUNDS .23. SYNTHESIS OF POLYHYDROXYLATED 2-PHENYLBENZOTHIAZOLES AND A COMPARISON OF THEIR CYTOTOXICITIES AND PHARMACOLOGICAL PROPERTIES WITH GENISTEIN AND QUERCETIN

被引:103
作者
STEVENS, MFG
MCCALL, CJ
LELIEVELD, P
ALEXANDER, P
RICHTER, A
DAVIES, DE
机构
[1] UNIV ASTON,INST PHARMACEUT SCI,BIRMINGHAM B4 7ET,W MIDLANDS,ENGLAND
[2] TNO,INST APPL RADIOBIOL & IMMUNOL,DIV HLTH RES,2280 HV RIJSWIJK,NETHERLANDS
[3] UNIV SOUTHAMPTON,SOUTHAMPTON GEN HOSP,CRC,MED ONCOL UNIT,SOUTHAMPTON S09 4XY,HANTS,ENGLAND
关键词
D O I
10.1021/jm00037a020
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of polyhydroxylated 2-phenylbenzothiazoles 3 has been prepared by demethylation of the precursor methoxylated 2-phenylbenzothiazoles 9. The key step in the construction of the benzothiazole nucleus involves a Jackson cyclization of methoxylated thiobenzanilides 8. The target compounds inhibit WiDr human colon tumor cells and MCF-7 human mammary tumor cells in vitro with IC50 values in the low micromolar range, but the activity against MCF-7 cells is not related to estrogen receptor-binding affinity. None of the compounds showed selective cytotoxicity against Abelson virus-transformed ANN-1 cells encoded with the pp120(gag-abl) tyrosine kinase compared with the parental 3T3 line. Compounds were only marginally inhibitory to the EGF receptor-associated protein tyrosine kinase from a membrane preparation of A431 cells. The most active compound was 4,6-dihydroxy-2-(4-hydroxyphenyl)benzothiazole (3b) which has the same overall hydroxyl substitution pattern as genistein (1a). The compounds were weakly cytotoxic for an EGF receptor, overexpressing cell line HN5, but when tested for differential toxicity against the EGF receptor tyrosine kinase or the PDGF receptor tyrosine kinase in a standard mitogenesis assay utilizing human fibroblasts, no discrimination was observed. In this assay, the compounds inhibited DNA synthesis when added to cells during S phase. This suggests that inhibition could not be interpreted in terms of tyrosine kinase inactivation but more likely as a relatively broad specificity for the ATP-binding domain of other kinases such as thymidine kinase.
引用
收藏
页码:1689 / 1695
页数:7
相关论文
共 23 条
[1]  
AKIYAMA T, 1987, J BIOL CHEM, V262, P5592
[2]  
CUNNINGHAM BDM, 1992, ANTI-CANCER DRUG DES, V7, P365
[3]   SYNTHESIS AND PROTEIN-TYROSINE KINASE INHIBITORY ACTIVITIES OF FLAVONOID ANALOGS [J].
CUSHMAN, M ;
NAGARATHNAM, D ;
BURG, DL ;
GEAHLEN, RL .
JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (02) :798-806
[4]  
ERBER S, 1991, ANTI-CANCER DRUG DES, V6, P417
[5]   PICEATANNOL (3,4,3',5'-TETRAHYDROXY-TRANS-STILBENE) IS A NATURALLY-OCCURRING PROTEIN-TYROSINE KINASE INHIBITOR [J].
GEAHLEN, RL ;
MCLAUGHLIN, JL .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1989, 165 (01) :241-245
[6]  
GEISSLER JF, 1992, CANCER RES, V52, P4492
[7]   THE EFFECT OF QUERCETIN ON THE PHOSPHORYLATION ACTIVITY OF THE ROUS-SARCOMA VIRUS TRANSFORMING GENE-PRODUCT INVITRO AND INVIVO [J].
GRAZIANI, Y ;
ERIKSON, E ;
ERIKSON, RL .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1983, 135 (03) :583-589
[8]   PREVALENCE OF ABERRANT EXPRESSION OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR IN HUMAN CANCERS [J].
GULLICK, WJ .
BRITISH MEDICAL BULLETIN, 1991, 47 (01) :87-98
[9]   THE USE OF POLYPHOSPHORIC ACID IN THE SYNTHESIS OF 2-ARYL-SUBSTITUTED AND 2-ALKYL-SUBSTITUTED BENZIMIDAZOLES, BENZOXAZOLES AND BENZOTHIAZOLES [J].
HEIN, DW ;
ALHEIM, RJ ;
LEAVITT, JJ .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1957, 79 (02) :427-429
[10]   CYTOFLUOROMETRIC DETERMINATION OF THYMIDINE KINASE-ACTIVITY IN A MIXTURE OF NORMAL AND NEOPLASTIC-CELLS [J].
HENGSTSCHLAGER, M ;
WAWRA, E .
BRITISH JOURNAL OF CANCER, 1993, 67 (05) :1022-1025