A new series of 2-(4-aminophenyl)benzothiazoles substituted in the phenyl ring and benzothiazole moiety has been synthesized by simple, high-yielding routes. The parent molecule 5a shows potent inhibitory activity in vitro in the nanomolar range against a panel of human breast cancer cell lines, but is inactive (IC50 > 30 microM) against other cell types: activity against the sensitive breast lines MCF-7 and MDA 468 is characterized by a biphasic dose-response relationship. Structure-activity relationships derived using these cell types has revealed that activity follows the heterocyclic sequence benzothiazole > benzoxazole >> benzimidazole and that 2-(4-aminophenyl)benzothiazoles bearing a 3'-methyl- 9a, 3'-bromo- 9c, 3'-iodo- 9f, and 3'-chloro-substituent 9i are especially potent and their activity extends to ovarian, lung, and renal cell lines. Four compounds have been evaluated in vivo against human mammary carcinoma models in nude mice. Compound 9a showed the most potent growth inhibition against the ER+ (MCF-7 and BO) and ER- (MT-1 and MT-3) tumors. Our efforts to identify a pharmacological mechanism of action for these intriguing compounds have not, as yet, been successful.

Summary 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 ,UM 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 G/M phase was observed. Two MCF-7 cell lines were established with acquired resistance to CJM 126 (IC50 values > 20 gM), 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.

Flow heterogeneity within capillary beds may have two sources: (1) unequal distribution of red blood cell (RBC) supply among arterioles and (2) unique properties of RBC flow in branching networks of capillaries. Our aim was to investigate the capillary network as a source of both spatial and temporal heterogeneity of RBC flow. Five networks, each supplied by a single arteriole, were studied in frog sartorius muscle (one network per frog) by intravital video microscopy. Simultaneous data on RBC velocity (millimeters per second), lineal density (RBCs per millimeter), and supply rate (RBCs per second) were measured continuously (10 samples per second) from video recordings in 5 to 10 capillary segments per network for 10 minutes by use of automated computer analysis. To quantify heterogeneity, mean values from successive 10-second intervals were tabulated for each flow parameter in each capillary segment (ie, portion of capillary between successive bifurcations), and percent coefficient of variation (SD/mean.100%) was calculated for (1) spatial heterogeneity among vessels (CVs) every 10 seconds and for the entire 10-minute sample and (2) temporal heterogeneity within vessels for every capillary segment and for the mean flow parameter. Analysis of these data indicates that (1) capillary networks are a significant source of both spatial and temporal flow heterogeneity, and (2) continuous redistributions of flow occur within networks, resulting in substantial temporal changes in CVs, although a persistent spatial heterogeneity of perfusion still exists on a 10-minute basis. In most networks, CVs decreased as supply rate within the network increased, thus indicating that rheology plays a significant role in determining the perfusion heterogeneity.

Arterial bifurcations in the cardiovascular system of a rat were studied, using a resin cast of the entire arterial tree. At each bifurcation, measurements were made of the diameters of the three vessels involved, the two branching angles, and the angle S, which the parent artery makes with the plane containing the two branches . The results were found to be consistent with those reported previously in man and monkey. In addition, measurements of S in the present study indicate that arterial bifurcations are mostly two dimensional .

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2-(4-Aminophenyl)benzothiazoles display potent and selective antitumor activity against inter alia breast, ovarian, colon, and renal cell lines, but their mechanism of action, though yet to be defined, may be novel. Metabolism is suspected to play a central role in the mode of action of these benzothiazoles since drug uptake and biotransformation were observed in sensitive cell lines (e.g., breast MCF-7 and MDA 468 cells) in vitro, whereas insensitive cell lines (e.g., prostate PC 3 cells) showed negligible uptake and biotransformation. N-Acyl derivatives of the arylamines have been synthesized, and in vitro studies confirm N-acetylation and oxidation as the main metabolic transformations of 2-(4-aminophenyl)benzothiazoles, with the predominant process being dictated by the nature of the 3'-substituent. The prototype amine 3 underwent mainly N-acetylation in vitro, while 3'-substituted analogues 4 and 5 were primarily oxidized. N-Acetylation of 4 to 11 exerts a drastic dyschemotherapeutic effect in vitro, but acetylation of the halogeno congeners 5-7 gave acetylamines 12-14 which substantially retain selective antitumor activity. In vivo pharmacokinetic studies in rats confirmed rapid and exclusive N-acetylation of the 3'-methyl analogue 4, but less acetylation with the 3'-chloro analogue 5. Distinct expression patterns of N-acetyltransferase NAT1 and NAT2 have been demonstrated in our panel of cell lines.

Summary 2-(4-Aminophenyl)benzothiazole molecules substituted in the 3 position of the phenyl ring with a halogen atom or methyl moiety comprise a group of compounds that potently inhibit specific human ovarian carcinoma cell lines. G150 values fall within the nm range. Inhibition is highly selective -whereas the G150 value in IGROV1 cells consistently lies at < 10 nM, SK-OV-3 presents G150 values > 10jIM. Biphasic dose-response relationships were observed in sensitive cell lines after 48-h drug exposure. COMPARE analyses revealed the very similar profiles of anti-tumour activity of 3-substituted benzothiazoles and 5-(4-dimethylaminophenylazo)quinoline, with Pearson correlation coefficients > 0.65. Anti-tumour activity extended to preliminary in vivo tests. The growth of OVCAR-3 cells in polyvinylidene fluoride (PVDF) hollow fibres implanted in the peritoneal cavity of mice was inhibited by more than 50% after intraperitoneal (i.p

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