Synthesis and identification of a new class of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzo[d]thiazole derivatives as potent antileukemic agents

Benzothiazoles are multitarget agents with broad spectrum of biological activity. Among the antitumor agents discovered in recent years, the identification of various 2-(4-aminophenyl) benzothiazoles as potent and selective antitumor drugs against different cancer cell lines has stimulated remarkable interest. Some of the benzothiazoles are known to induce cell cycle arrest, activation of caspases and interaction with DNA molecule. Based on these interesting properties of benzothiazoles and to obtain new biologically active agents, a series of novel 4,5,6,7-tetrahydrobenzo[d]thiazole derivatives 5(a-i) were synthesized and evaluated for their efficacy as antileukemic agents in human leukemia cells (K562 and Reh). The chemical structures of the synthesized compounds were confirmed by H-1 NMR, LCMS and IR analysis. The cytotoxicity of these compounds were determined using trypan blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Results showed that, these compounds mediate a significant cytotoxic response to cancer cell lines tested. We found that the compounds having electron withdrawing groups at different positions of the phenyl ring of the thiourea moiety displayed significant cytotoxic effect with IC50 value less than 60 mu M. To rationalize the role of electron withdrawing group in the induction of cytotoxicity, we have chosen molecule 5g (IC50 similar to 15 mu M) which is having chloro substitution at ortho and para positions. Flow cytometric analysis of annexin V-FITC/ propidium iodide (PI) double staining and DNA fragmentation suggest that 5g can induce apoptosis.

A mixed-split scheme for 2-D DPCM based LSF quantization

In this paper a mixed-split scheme is proposed in the context of 2-D DPCM based LSF quantization scheme employing split vector product VQ mechanism. Experimental evaluation shows that the new scheme is successfully being able to show better distortion performance than existing safety-net scheme for noisy channel even at considerably lower search complexity, by efficiently exploiting LSF trajectory behavior across the consecutive speech frames.

Synthesis of enantiopure bis-aziridines, bis-epoxides, and aziridino-epoxides from D-mannitol

A practical synthesis of enantiopure bis-aziridines 11 and 15, bis-epoxides 12 and 17, and aziridino-epoxides 27 and 30 is reported using inexpensive d-mannitol as the starting material. The key transformation involves the reductive cleavage of bis-benzylidene acetal 3 to form dimesylate 4, which was further converted to monoazides and diazides followed by reduction, mesylation, and cyclization to furnish the required compounds in good yields.

Purification and characterization of an alpha-D-glucuronidase from a thermophilic fungus, Thermoascus aurantiacus

An alpha-D-glucuronidase was purified from the culture filtrates of Thermoascus aurantiacus. A simple colorimetric method for its assay is reported. The enzyme is a single polypeptide chain with a molecular weight of 118,000. It acts optimally at pH 4.5. It shows maximum activity at 65 degrees C. The t 1/2 at 70 degrees C was 40 min. It specifically cleaved the alpha-(1----2) linkage between 4-O-methyl-alpha-D-glucuronic acid and the xylose residue in xylan and several glucurono-xylooligosaccharides.

Peptide hairpin nucleation with the obligatory Type I' beta-turn Aib-(D)Pro segment

The alpha-aminoisobutyric acid-D-proline (Aib-(D)Pro) dipeptide is an obligatory Type I' beta-turn forming segment that nucleates hairpin formation.

Computer modelling approach to study the modes of binding of alpha- and beta-anomers of D-galactose, D-fucose and D-glucose to L-arabinose-binding protein

The modes of binding of alpha- and beta-anomers of D-galactose, D-fucose and D-glucose to L-arabinose-binding protein (ABP) have been studied by energy minimization using the low resolution (2.4 A) X-ray data of the protein. These studies suggest that these sugars preferentially bind in the alpha-form to ABP, unlike L-arabinose where both alpha- and beta-anomers bind almost equally. The best modes of binding of alpha- and beta-anomers of D-galactose and D-fucose differ slightly in the nature of the possible hydrogen bonds with the protein. The residues Arg 151 and Asn 232 of ABP from bidentate hydrogen bonds with both L-arabinose and D-galactose, but not with D-fucose or D-glucose. However in the case of L-arabinose, Arg 151 forms hydrogen bonds with the hydroxyl group at the C-4 atom and the ring oxygen, whereas in case of D-galactose it forms bonds with the hydroxyl groups at the C-4 and C-6 atoms of the pyranose ring. The calculated conformational energies also predict that D-galactose is a better inhibitor than D-fucose and D-glucose, in agreement with kinetic studies. The weak inhibitor D-glucose binds preferentially to one domain of ABP leading to the formation of a weaker complex. Thus these studies provide information about the most probable binding modes of these sugars and also provide a theoretical explanation for the observed differences in their binding affinities.

Role of hydroxyl group on the mesomorphism of alkyl glycosides:synthesis and thermal behavior of alkyl 6-deoxy-beta-D-glucopyranosides

A homologous series of alkyl 6-deoxy-beta-D-glucopyranoside amphiphiles was prepared,in an effort to identify the role of hydroxyl group in the mesomorphic behavior of alkyl glycosides. Synthesis was performed by a chlorination of the sugar moiety in alkyl-beta-D-glucopyranosides with methylsulfonyl chloride in DMF, followed by a metal mediated dehalogenation to secure alkyl 6-deoxy-beta-D-glucopyranosides, wherein the alkyl chain length varied from C-9 to C-16. The mesomorphic behavior of these 6-deoxy alkyl glycosides was assessed using polarizing optical microscopy, differential scanning calorimetry and X-ray diffraction method. Whereas the lower homologues exhibited a monotropic SmA phase till sub-ambient temperatures, the higher homologues formed a plastic phase. A partial interdigitized bilaye structure of SmA phase is inferred from experimental d-spacing and computationally derived lengths of the molecules. The results were compared with those of normal alkyl glucopyranosides, retained with hydroxyl groups at C-2-C-6 carbons, and alkyl 2-deoxy-glucopyranosides, devoid of a hydroxyl group at C-2 and the comparison showed important differences in the mesomorphic behavior.(C)2010 Elsevier Ireland Ltd. All rights reserved.

Synthesis and Antileukemic Activity of 1-((S)-2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-3-(substituted phenyl)urea Derivatives

Heterocyclic urea derivatives play an important role as anticancer agents because of their good inhibitory activity against receptor tyrosine kinases (RTKs), raf kinases, protein tyrosine kinases (PTKs), and NADH oxidase, which play critical roles in many aspects of tumorigenesis. Benzothiazole moiety constitutes an important scaffold of drugs, possessing several pharmacological functions, mainly the anticancer activity. Based on these interesting properties of benzothiazoles and urea moiety to obtain new biologically active agents, we synthesized a series of novel 1-((S)-2-amino-4,5,6.7-tetrahydrobenzo[d]thiazol-6-yl)-3-(substituted phenyl)urea derivatives and evaluated for their efficacy as antileukemic agents against two human leukemic cell lines (K562 and Reh). These compounds showed good and moderate cytotoxic effect to cancer cell lines tested. Compounds with electron-withdrawing chloro and fluoro substituents on phenyl ring showed good activity and compounds with electron-donating methoxy group showed moderate activity. Compound with electron-withdrawing dichloro substitution on phenyl ring of aryl urea showed good activity. Further, lactate dehydrogenase (LDH) assay, flow cytometric analysis of annexin V-FITC/propidium iodide (PI) double staining and DNA fragmentation studies showed that compound with dichloro substitution on phenyl ring of aryl urea can induce apoptosis.

Chiral synthons from carvone, Part 40. A simple, enantiospecific approach to both enantiomers of 1 alpha,25-dihydroxyvitamin D-3 A-ring precursors from R-carvone

A simple and direct approach to both enantiomeric series of A-ring derivatives of 1 alpha,25-dihydroxyvitamin D-3 and the corresponding 1 alpha,3 alpha-derivatives, starting from the abundantly available R-carvone, is described. (C) 2000 Elsevier Science Ltd. All rights reserved.

Studies on follicular atresia: role of gonadotropins and gonadal steroids in regulating cathepsin-D activity of preovulatory follicles in the rat

Preovulatory follicular atresia was studied using pregnant mare serum gonadotropin (PMSG)-primed rats (15 IU/rat) which were deprived of hormonal support either by allowing the metabolic clearance of the PMSG or by injecting a specific PMSG antiserum (PMSG a/s). Atresia was monitored by an increase in lysosomal cathepsin-D activity and a decrease in the receptor activity of the granulosa cells (GC) isolated from the preovulatory follicles. It was shown that the increase in lysosomal activity and the decrease in receptor activity seen at 96 h after PMSG (or PMSG plus PMSG a/s) could be arrested both by follicle stimulating hormone (FSH) and luteinizing hormone (LH). Injection of cyanoketone or clomiphene citrate together with FSH/LH prevented this 'rescue' suggesting a role for estrogens in the regulation of atresia. Although the administration of estradiol-17 beta (20 micrograms/rat) together with PMSG a/s could show a 'rescue effect' in terms of reduction in cathepsin-D activity the gonadotropin receptor activities of these granulosa cells were not restored. The injection of dihydrotestosterone (DHT) to 48 h PMSG-primed rats induced atresia as noted by an increase in cathepsin-D activity. However, the exogenous administration of FSH along with DHT prevented this atretic effect suggesting that DHT is not having a direct effect on atresia. Determination of androgen: estrogen content of the granulosa cells and an analysis of the individual profile of androgen and estrogen revealed that the increase in cathepsin-D activity could be correlated only with the decrease in GC estrogen content. This along with the observation that GC showed a loss of estrogen synthesis well before the increase in cathepsin-D activity strongly points out that the lack of estrogen rather than an increase in androgen is the principle factor responsible for the atresia of preovulatory follicles in the rat.

The first D-pi-A octupolar cryptand molecule to exhibit bulk non-linearity

The cryptand derivative has H-bond mediated trigonal network structure that leads to octupolar bulk nonlinearity.

New a posteriori error estimator and adaptive mesh refinement strategy for 2-D crack problems

A posteriori error estimation and adaptive refinement technique for fracture analysis of 2-D/3-D crack problems is the state-of-the-art. The objective of the present paper is to propose a new a posteriori error estimator based on strain energy release rate (SERR) or stress intensity factor (SIF) at the crack tip region and to use this along with the stress based error estimator available in the literature for the region away from the crack tip. The proposed a posteriori error estimator is called the K-S error estimator. Further, an adaptive mesh refinement (h-) strategy which can be used with K-S error estimator has been proposed for fracture analysis of 2-D crack problems. The performance of the proposed a posteriori error estimator and the h-adaptive refinement strategy have been demonstrated by employing the 4-noded, 8-noded and 9-noded plane stress finite elements. The proposed error estimator together with the h-adaptive refinement strategy will facilitate automation of fracture analysis process to provide reliable solutions.

Interaction between the Z-type DNA duplex and 1,3-propanediamine:crystal structure of d(CACGTG)(2) at 1.2 angstrom resolution

The crystal structure of a hexamer duplex d(CACGTG)(2) has been determined and refined to an R-factor of 18.3% using X-ray data up to 1.2 angstrom resolution. The sequence crystallizes as a left-handed Z-form double helix with Watson-Crick base pairing. There is one hexamer duplex, a spermine molecule, 71 water molecules, and an unexpected diamine (Z-5, 1,3-propanediamine, C3H10N2)) in the asymmetric unit. This is the high-resolution non-disordered structure of a Z-DNA hexamer containing two AT base pairs in the interior of a duplex with no modifications such as bromination or methylation on cytosine bases. This structure does not possess multivalent cations such as cobalt hexaammine that are known to stabilize Z-DNA. The overall duplex structure and its crystal interactions are similar to those of the pure-spermine form of the d(CGCGCG)(2) structure. The spine of hydration in the minor groove is intact except in the vicinity of the T5A8 base pair. The binding of the Z-5 molecule in the minor grove of the d(CACGTG)(2) duplex appears to have a profound effect in conferring stability to a Z-DNA conformation via electrostatic complementarity and hydrogen bonding interactions. The successive base stacking geometry in d(CACGTG)(2) is similar to the corresponding steps in d(CG)(3). These results suggest that specific polyamines such as Z-5 could serve as powerful inducers of Z-type conformation in unmodified DNA sequences with AT base pairs. This structure provides a molecular basis for stabilizing AT base pairs incorporated into an alternating d(CG) sequence.