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A number of indolyl thiazoles have been prepared and evaluated for their antitumor properties. The compounds were synthesized from the appropriate indole, building up the thiazole ring using the Hantzsch reaction. Cytotoxic activity was measured in the human breast cancer cell line SKBr3 using the MTT assay.
In order to characterize the structural elements that might play a role in non-covalent DNA binding by the antitumor antibiotic leinamycin, we have solved the crystal structures of the two leinamycin analogs, methyl (R)-5-[2-[1-(tert-butoxycarbonylamino)ethyl]thiazol-4-yl]penta-(E,E)-2,4-dienoate, C(16)H(22)N(2)O(4)S, (II), and 2-methyl-8-oxa-16-thia-3,17-diazabicyclo[12.2.1]heptadeca-(Z,E)-1(17),10,12,14-tetraene-4,9-dione, C(14)H(16)N(2)O(3)S, (III). The penta-2,4-dienone moiety in both of these analogs adopts a conformation close to planarity, with the thiazole ring twisted out of the plane by 12.9 (2) degrees in (II) and by 21.4 (4) degrees in (III).
The title compounds, C(13)H(15)N(3)O(5)S and C(11)H(10)N(2)O(4)S(2), respectively, both contain a phenylsulfonyl group connected, through a methylene bridge, to either a substituted nitroimidazole or nitro-1,3-thiazole ring. In the imidazole-containing molecule, the nitro and sulfonyl groups are trans relative to the sulfonyl-methyl bond, while in the thiazole-containing molecule, these substituents are cis. The stabilizing interactions within the crystals are also different between the two compounds.
Thiazole orange is a new fluorescent dye which will bind to the residual RNA in the cytoplasm of reticulocytes and allow their enumeration by FACS analysis. We have evaluated the use of this dye in the routine haematology laboratory. There is an excellent correlation between manual and FACS reticulocyte counts (r = 0.98) but FACS counting showed significantly higher precision (CV = 3.1) than the manual method (CV = 11.9) for single observer, 20.8% for multiple observers). Clinical specimens showed stable reticulocyte counts for 6 h if stored at 4 degrees C allowing efficient batching of samples. There was a significant fall in reticulocyte counts stored for 24 h at both 4 degrees C and 21 degrees C. Evaluation of 78 male and 76 female blood donors by FACS analysis gave normal ranges (mean % +/- 2 SD) of 0.74 +/- 0.48 and 0.84 +/- 0.56 respectively (P less than 0.005). When corrected to absolute values there was no sex difference (36 +/- 24 x 10(9)/l). Thiazole orange is an effective stain for the automated counting of reticulocytes by FACS analysis.
We have previously proposed that the BlmIV and BlmIII non-ribosomal peptide synthetases are involved in the formation of the bithiazole moiety of the anti-tumor drug bleomycin in Streptomyces verticillus ATCC15003. We report here the identification and characterization of an oxidation domain in BlmIII. The oxidation domain shows local homology to a family of oxidoreductases and is present in all thiazole-forming non-ribosomal peptide synthetase modules known to date. Both the blmIII-Ox domain and blmIII gene were expressed in Escherichia coli, and the resulting BlmIII-Ox and BlmIII proteins were purified to homogeneity. The oxidation domain contains one molar equivalent of non-covalently bound FMN as a prosthetic group. These results provide experimental evidence for an oxidation domain within non-ribosomal peptide synthetases, suggesting that BlmIII-Ox probably catalyzes the thiazoline to thiazole oxidation in bleomycin biosynthesis.
Glycine was found to replace thiamine thiazole for the growth of the thiazoleless mutant of Escherichia coli; it also stimulated the production of thiamine thiazole by washed cell suspensions of the mutant.
Two independent methods for quantitating reticulocyte counts were compared. One used a modified thiazole orange technique and a flow cytometer (Becton Dickinson FACS); the other was a fully automated whole blood analyser (Sysmex R1000). Both methods gave comparable results with a coefficient of variation of less than 5%. Samples measured using the R1000 showed a negligible decrease in the reticulocyte count over five days at room temperature, although there was evidence of continuing intracellular maturation: with thiazole orange there was an apparent increase. A practical reference range of 20-70 x 10(9)/l was established from 89 normal subjects. The close correlation between the two independent estimates indicates the validity of the quantitation of the reticulocyte count and shows that automation allows significant changes within and below the normal range to be detected with a degree of reliability which was not previously possible.
A series of 2-[4-(thiazol-2-yl)phenyl]propionic acids substituted at various positions were prepared by the reaction of diethyl 2-methyl-2-(4-thiocarbamoylphenyl)malonates with alpha-bromoaldehyde diethyl acetals or alpha-haloketones followed by hydrolysis of esters. The inhibition of prostaglandin H synthetase (cyclooxygenase) was assayed by use of an enzyme preparation from guinea pig polymorphonuclear leukocytes. Examination of the structure-activity relationship of these compounds indicated that the substitution pattern with halogens at position 3 (R1) of the benzene ring and a methyl group in position 4 (R2) and/or 5 (R3) of the thiazole ring were favorable for inhibitory activity. The compounds bearing bulky alkyl or polar functional groups at the R2 position were weak inhibitors. The potent inhibitors of cyclooxygenase were tested for their ability to reduce carrageenin-induced inflammation of rat paws. These derivatives had strong anti-inflammatory activity based on their strong inhibition of cyclooxygenase, with some exceptions, including those with a thiomethyl group at R1.
The photo-stability of ethyl 2-[4,5-bis(4-methoxyphenyl)thiazole-2-yl]pyrrol-1-ylacetate, KBT-3022 in aqueous solutions containing acetonitrile was investigated under the light of a high pressure mercury lamp. Its main photo-degradation product was assumed to be ethyl 5-hydroxy-5-[4,5-bis(4-methoxyphenyl)thiazole-2-yl]-2-oxo-3-pyrrolin+ ++-1-ylacetate. KBT-3022 was also found to undergo ester hydrolysis by heat in both acidic and basic aqueous solutions, but its hydrolysis was confirmed to be negligible in the range of pH 3-9 at room temperature (25 degrees C). Further, its photo-stability with exposure to the high pressure mercury lamp was comparable to that with exposure to a fluorescent lamp. Therefore, it is considered feasible to simulate the photo-stability of KBT-3022 in aqueous solutions containing acetonitrile by exposure to all other light sources including diffuse daylight, if the cumulative number of photons of the light can be determined by actinometry.
A new series of thiazole-containing triazole antifungals was synthesized and evaluated for antifungal activity against a variety of clinically isolated pathogenic fungi in vitro and against systemic candidosis in vivo. Among these compounds, (+/-)-1-(2,4-difluorophenyl)-1-[4-(2,4-difluorophenyl) thiazol-2-yl]-2-(1H-1,2,4-triazol-1-yl)ethanol (ER24161) showed the most potent and well-balanced in vitro activities and excellent in vivo efficacy. We also achieved an enantioselective synthesis of the more potent enantiomer of ER-24161.
A series of novel thiazole-containing triazole antifungals was synthesized and evaluated for antifungal activity against a variety of clinically isolated pathogenic fungi in vitro and against systemic candidosis in vivo. These compounds showed potent antifungal activities in vitro and in vivo. In particular, (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4- difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (12g; ER-30346) showed potent and well-balanced in vitro activities and potent in vivo efficacy, and had a good safety profile.
A series of 8H-indeno[1,2-d]thiazoles containing various N-substituted amino groups at the 2 position were synthesized by the reaction of 2-bromo-indanones and N-substituted thioureas. Their anti-ulcerous activity was evaluated. Alkylamino derivatives have a more potent inhibitory behavior on ethanol-induced gastric ulcers compared with arylamino derivatives. We also studied the effect of various substituents on the both benzene and pyridine ring of 2-pyridylamino derivatives on ethanol-induced gastric ulcers. However no clear effects were observed. Among 3-morpholinopropylamino derivatives, 5-isopropyl- (21) and 7-chloro-2-(3-morpholinopropyl)amino-8H-indeno[1,2-d]thiazole (25) showed a considerably stronger inhibitory behavior on hydrochloric acid-induced gastric ulcers than cetraxate hydrochloride. Furthermore, 3-morpholinopropylamino derivatives have potent inhibitory effects on gastric acid secretion in pylorus ligated rats.
"Light-up" probes, icosa-alpha-thymidylate-thiazole orange conjugates, for the in situ time-resolved detection of messenger ribonucleic acid (mRNA) in living cells are evaluated. Upon annealing with polyA in aqueous solutions, the icosa-alpha-thymidylate-thiazole orange conjugates were shown to be up to 15 times more fluorescent. Microinjection of these probes into adherent fibroblasts resulted in high yields of hybridization and fluorescent signals. Incubation of cells in the presence of these probes resulted in facile internalization of the probe and similar painting of the messenger RNA in the nuclear and cytosolic regions.
The synthesis and microbiological evaluation of a new series of 3-thiazol-4-yl-carba-1-dethiacephalosporins is described. Structure activity relationship was achieved by changing substitution at the 2-position of the thiazole moiety. The result was a marked variance of microbiological activity in the C7 side-chain derivatives. ATMO derivatives possess potent activity against both Gram-positive and Gram-negative bacteria. For example, MICs (microgram/ml) of LY215226 against representative organisms are as follows: S. aureus 0.25, S. pneumoniae 0.008, H. influenzae 0.008, E. coli 0.25, K. pneumoniae 0.008, E. cloacae 0.5, S. typhi 0.25, and M. morganii 0.25.
New 6,7-dialkoxy-2-arylmethylidene-2,3- dihydrobenzo[4,5]imidazo[2,1-b][1,3]thiazol-3-ones (3a-h, 4b, c, e, g) were synthesized from 2-(5,6-dialkoxy-1H-benzo[d]imidazol-2-ylsulfanyl)acetic acids (1, 2) and corresponding aromatic aldehydes in acetic anhydride. The compounds 3e, f and 4b, g were also synthesized from corresponding aromatic aldehydes and 6,7-dialkoxy-2,3-dihydrobenzo[4,5]imidazo[2,1-b][1,3]thiazol -3-ones (5, 6) obtained by the cyclization of the acids 1 and 2 in acetic anhydride. The synthesized compounds 3a-h and 4b, c, e, g exhibit anti-inflammatory activity.
It was shown that the thiazole derivative 3-decyloxycarbonylmethyl-4-methyl- 5-(2-hydroxyethyl)thiazole chloride (DMHT) (0.1 mM) reversibly reduced the transmembrane current in solutions of 10 mM CaCl2 and 100 mM KCl via ionic channels produced by alpha-latrotoxin from black widow spider (alpha-LT) and sea anemone toxin (RTX) in the bilayer lipid membranes (BLM). Introduction of DMHT from the cis-side of BLM inhibited transmembrane current by 31.6 +/- 3% and by 61.8 +/- 3% from the trans-side of BLM for alpha-LT channels. Application of DMHT to the cis-side BLM decreased the inward current through the RTX channels by 50 +/- 5%. Addition of Cd(2+) (0.1 mM) to the cis- or trans-side of a membrane after the DMHT induced depression of transmembrane current across the alpha-LT channels caused its further decrease by 85 +/- 5% that coincides completely with the intensity of Cd(2+)-inhibition in the control experiments without DMHT. These data suggest that DMHT may exert its inhibitory action on alpha-LT channels without considerable influence on the ionogenic groups inside the channel cavity. The comparative analysis of effective radii measured for alpha-LT and RTX channels on the cis- (0.9 nm and 0.55 nm, respectively) and the trans-side of BLM (< 0.467 nm for alpha-LT) allowed to propose the blocking action of DMHT for alpha-LT and RTX channels to result from direct penetration into the channel, achieved due to similar hydrodynamic size of blocking molecules and the size of toxin pores.
An automated reticulocyte counting method that used a flow cytometer and the nucleic acid staining dye, thiazole orange, was developed. Anticoagulated (EDTA) blood specimens were suitable for flow cytometric reticulocyte counting when stored at 4 C for 96 hours after collection. Thiazole orange-stained samples were stable for 5.5 hours after staining when stored capped at 20 C and protected from light. Flow cytometric and manual microscopic reticulocyte counts were compared for counts in the 0.27 to 5.32% range (as determined by flow cytometry) and 0.10 to 4.90% range (as determined by 1 technician). Although the results of flow cytometric analysis generally correlated well (r = 0.821) with manual counts, there was poor correlation between the procedures for counts less than or equal to 2.0% (r less than or equal to 0.272). Linearity of flow cytometric counts over the range 0.27 to 14.46% was excellent (r = 0.999). Within-run precision of flow cytometric counts (% coefficient of variation [cv] = 3 to 5) was superior to manual microscopic counts obtained by one technician (% cv = 19 to 23) and to manual microscopic counts, which were an average of counts done by 3 technicians (% cv = 8 to 18). Comparable flow cytometric counts were obtained by counting 50,000 or 100,000 blood cells in the flow cytometer.
Flow cytometric reticulocyte quantification with thiazole orange has been reported to be of potential utility in a clinical hematology laboratory. We have instituted this technique into routine clinical testing for 18 months and we describe this experience. Flow cytometric analysis provided not only reproducible, cost-effective reticulocyte quantification, but a quantitative reticulocyte maturity index proportional to the amount of RNA in the reticulocytes. The reticulocyte maturity index measurement represents an independent parameter of erythropoiesis, which provided clinically valuable information regarding bone marrow engraftment in patients following autologous bone marrow transplantation. The findings of this study demonstrate the clinical utility of thiazole orange reticulocyte analysis and indicate the diagnostic importance of the reticulocyte maturity index measurement in the evaluation of erythropoietic activity.