Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1998 Mar;77(5):745–752. doi: 10.1038/bjc.1998.122

2-(4-Aminophenyl)benzothiazoles: novel agents with selective profiles of in vitro anti-tumour activity.

T D Bradshaw 1, S Wrigley 1, D F Shi 1, R J Schultz 1, K D Paull 1, M F Stevens 1
PMCID: PMC2149949  PMID: 9514053

Abstract

2-(4-Aminophenyl)benzothiazole (CJM 126) elicits biphasic growth-inhibitory effects against a panel of oestrogen receptor-positive (ER+) and oestrogen receptor-negative (ER-) human mammary carcinoma cell lines in vitro, yielding IC50 values in the nM range. Substitutions adjacent to the amino group in the 2-phenyl ring with a halogen atom or methyl group enhance potency in sensitive breast lines (pM IC50 values). Transient biphasic dose responses were induced but rapidly eradicated after specific drug exposure periods. Two human prostate carcinoma cell lines were refractory to the growth-inhibitory properties of 2-(4-aminophenyl)benzothiazoles; IC50 values > 30 microM were obtained. Potency and selectivity were confirmed when compounds were examined in the National Cancer Institute's Developmental Therapeutics screen; the spectrum of activity included specific ovarian, renal, colon as well as breast carcinoma cell lines. Moreover, comparing 6-day and 48-h incubations, the exposure time-dependent nature of the biphasic response was corroborated. Differential perturbation of cell cycle distribution followed treatment of MCF-7 and MDA 468 cells with substituted 2-(4-aminophenyl)benzothiazoles. In MDA 468 populations only, accumulation of events in G2/M phase was observed. Two MCF-7 cell lines were established with acquired resistance to CJM 126 (IC50 values > 20 microM), which exhibit cross-resistance to substituted benzothiazoles, but equal sensitivity to tamoxifen and doxorubicin. Compared with standard anti-tumour agents evaluated in the National Cancer Institute in vitro cell panel, benzothiazoles revealed unique profiles of growth inhibition, suggesting a mode(s) of action shared with no known clinically active class of chemotherapeutic agents.

Full text

PDF
745

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akama T., Shida Y., Sugaya T., Ishida H., Gomi K., Kasai M. Novel 5-aminoflavone derivatives as specific antitumor agents in breast cancer. J Med Chem. 1996 Aug 30;39(18):3461–3469. doi: 10.1021/jm950938g. [DOI] [PubMed] [Google Scholar]
  2. Hotz M. A., Del Bino G., Lassota P., Traganos F., Darzynkiewicz Z. Cytostatic and cytotoxic effects of fostriecin on human promyelocytic HL-60 and lymphocytic MOLT-4 leukemic cells. Cancer Res. 1992 Mar 15;52(6):1530–1535. [PubMed] [Google Scholar]
  3. Leathwood P. D., Plummer D. T. Enzymes in rat urine. I. A metabolism cage for the complete separation of urine and faeces. Enzymologia. 1969 Oct 31;37(4):240–250. [PubMed] [Google Scholar]
  4. Nicoletti I., Migliorati G., Pagliacci M. C., Grignani F., Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 1991 Jun 3;139(2):271–279. doi: 10.1016/0022-1759(91)90198-o. [DOI] [PubMed] [Google Scholar]
  5. Pagliacci M. C., Smacchia M., Migliorati G., Grignani F., Riccardi C., Nicoletti I. Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF-7 human breast cancer cells. Eur J Cancer. 1994;30A(11):1675–1682. doi: 10.1016/0959-8049(94)00262-4. [DOI] [PubMed] [Google Scholar]
  6. Pickard M., Dive C., Kinsella A. R. Differences in resistance to 5-fluorouracil as a function of cell cycle delay and not apoptosis. Br J Cancer. 1995 Dec;72(6):1389–1396. doi: 10.1038/bjc.1995.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Sadrieh N., Davis C. D., Snyderwine E. G. N-acetyltransferase expression and metabolic activation of the food-derived heterocyclic amines in the human mammary gland. Cancer Res. 1996 Jun 15;56(12):2683–2687. [PubMed] [Google Scholar]
  8. Seelig M. H., Berger M. R. Efficacy of dinaline and its methyl and acetyl derivatives against colorectal cancer in vivo and in vitro. Eur J Cancer. 1996 Oct;32A(11):1968–1976. doi: 10.1016/0959-8049(96)00217-1. [DOI] [PubMed] [Google Scholar]
  9. Shi D. F., Bradshaw T. D., Wrigley S., McCall C. J., Lelieveld P., Fichtner I., Stevens M. F. Antitumor benzothiazoles. 3. Synthesis of 2-(4-aminophenyl)benzothiazoles and evaluation of their activities against breast cancer cell lines in vitro and in vivo. J Med Chem. 1996 Aug 16;39(17):3375–3384. doi: 10.1021/jm9600959. [DOI] [PubMed] [Google Scholar]
  10. Stevens M. F., McCall C. J., Lelieveld P., Alexander P., Richter A., Davies D. E. Structural studies on bioactive compounds. 23. Synthesis of polyhydroxylated 2-phenylbenzothiazoles and a comparison of their cytotoxicities and pharmacological properties with genistein and quercetin. J Med Chem. 1994 May 27;37(11):1689–1695. doi: 10.1021/jm00037a020. [DOI] [PubMed] [Google Scholar]
  11. Weinstein J. N., Myers T. G., O'Connor P. M., Friend S. H., Fornace A. J., Jr, Kohn K. W., Fojo T., Bates S. E., Rubinstein L. V., Anderson N. L. An information-intensive approach to the molecular pharmacology of cancer. Science. 1997 Jan 17;275(5298):343–349. doi: 10.1126/science.275.5298.343. [DOI] [PubMed] [Google Scholar]
  12. Yang J. H., Rhim J. S. 2,3,7,8-Tetrachlorodibenzo-p-dioxin: molecular mechanism of carcinogenesis and its implication in human in vitro model. Crit Rev Oncol Hematol. 1995 Feb;18(2):111–127. doi: 10.1016/1040-8428(94)00125-d. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES