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.

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.

Effect of phenoxy acids and their derivatives on lipid metabolism in groundnut (Arachis hypogaea) leaves

The effect of four phenoxy compounds [2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid, 4-chlorophenoxyacetic acid 2-(dimethylamino)ethyl ester (centrophenoxine), and 4-chlorophenoxy ethyl 2-(dimethylamino) ethyl ether (neophenoxine)] on lipid metabolism in groundnut (Arachis hypogaea) leaves was investigated under nonphotosynthetic conditions. In experiments with leaf disks, the uptake of [1-14C]acetate, [32P]orthophosphate, [35S]sulfate and [methyl-14C]choline was substantially inhibited by all the phenoxy compounds except neophenoxine. When the incorporation of these precursors into lipids was measured and expressed as percentage of total uptake, there was significant inhibition of incorporation of [1-14C]acetate and [32P]orthophosphate into lipids by all the compounds except neophenoxine. The incorporation of [methyl-14C]choline was unaffected by all except centrophenoxine which showed stastically significant stimulation. [35S]Sulfate incorporation into lipids was markedly inhibited only by centrophenoxine. The fatty acid synthetase of isolated chloroplasts assayed in the absence of light was inhibited 20–50% by the phenoxy compounds at 0.5 mM concentration. This inhibition showed a dependence on time of preincubation with the herbicide suggesting an interaction with the enzyme. It was, however, reversible and excess substrate did not prevent the inhibition, suggesting that the herbicide interaction may not be at the active site. sn-Glycerol-3-phosphate acyltransferase in the chloroplast and microsomal fractions was inhibited by 2,4-D while the phosphatidic acid phosphatase was insensitive to all the phenoxy compounds. It is concluded that phenoxy compounds affect precursor uptake, their incorporation into lipids, and the chloroplast fatty acid synthetase. The free acids were the most potent compounds while the ester (centrophenoxine) was less effective and the ether (neophenoxine) was completely ineffective in their influence on lipid metabolism.

Preparation and characterization of hydrazinium derivatives

A number of simple and complex hydrazinium derivatives have been prepared by the reaction of hydrazine hydrate with ammonium salts. The products were characterized by chemical analysis and infrared spectra.

Rearrangement of homobrendane derivatives. Total syntheses of racemic copacamphor, ylangocamphor, and their homologs

Rearrangement of a homobrendane derivative 8a to perhydro-1,4-methanoindenesy stem 9a could be brought about either by p-toluenesulfonic acid or boron trifluoride etherate. Similarly, rearrangement of 8b-d led to the formation of perhydro-1,4-methanoindened erivatives 9b-d. On the basis of the location of substituents in the starting material and the product, a probable mechanistic pathway has been suggested. The appropriate modification of the peripheral functionalities in 9 led to efficient total syntheses of (f)-copacamphor (15a),(f)-ylangocamphor (16a), and their homologues 15b and 16b.

Crystallographic characterization of the conformation of the 1-aminocyclohexane-1-carboxylic acid residue in simple derivatives and peptides

The crystal structures of 1-aminocyclohexane-1-carboxylic acid (H-Acc6-OH) and six derivatives (including dipeptides) have been determined. The derivatives are Boc-Acc6-OH, Boc-(Acc6)2-OH, Boc-L-Met-Acc6-OMe, ClCH2CO-Acc6-OH, p-BrC6H4CO-Acc6-OH oxazolone, and the symmetrical anhydride from Z-Acc6-OH, [(Z-Acc6)2O]. The cyclohexane rings in all the structures adopt an almost perfect chair conformation. The amino group occupies the axial position in six structures; the free amino acid is the only example where the carbonyl group occupies an axial position. The values determined for the torsion angles about the N–Cα(φ) and Cα–CO (ψ) bonds correspond to folded, potentially helical conformations for the Acc6 residue.

Analysis of Cl center dot center dot center dot Cl and C-H center dot center dot center dot Cl intermolecular interactions involving chlorine in substituted 2-chloroquinoline derivatives

Six crystal structures of substituted 2-chloroquinoline derivatives have been analysed to evaluate the role of Cl atom as a self recognizing unit resulting in the formation of Cl center dot center dot center dot Cl and C-H center dot center dot center dot Cl interactions to generate supramolecular assembly in the solid state. The features of Type I and Type II geometries associated with Cl center dot center dot center dot Cl interactions have been analysed to show directional preferences leading to differences in the packing motifs in these crystal structures. C-H center dot center dot center dot Cl interactions are generated exclusively in structures depicting Type II Cl center dot center dot center dot Cl interaction have been observed in these structures.

Interaction of nitrogen with fullerenes: nitrogen derivatives of C60 and C70

On the basis of N(1s) core-level spectroscopic studies, it is found that nitrogen interacts with multimolecular films of C60. More interestingly, mass spectrometric studies show that contact-arc vaporization of graphite in a partial atmosphere of N2 or NH3 yields nitrogenous products tentatively assigned to species such as C70N2, C59N6, C59N4, and C59N2 involving addition of or substitution by nitrogen along with the species due to C2 and C4 losses.

Octabromotetraphenylporphyrin and its metal derivatives: Electronic structure and electrochemical properties

The free-base octabromotetraphenylporphyrin (H2OBP) has been prepared by a novel bromination reaction of (meso-tetraphenylporphyrinato)copper(II). The metal [V(IV)O, Co(II), Ni(II), Cu(II), Zn(II), Pd(II), Ag(II), Pt(II)] derivatives exhibit interesting electronic spectral features and electrochemical redox properties. The electron-withdrawing bromine substituents at the pyrrole carbons in H2OBP and M(OBP) derivatives produce remarkable red shifts in the Soret (50 nm) and visible bands (100 nm) of the porphyrin. The low magnitude of protonation constants (pK3 = 2.6 and pK4 = 1.75) and the large red-shifted Soret and visible absorption bands make the octabromoporphyrin unique. The effect of electronegative bromine substituents at the peripheral positions of the porphyrin has been quantitatively analyzed by using the four-orbital approach of Gouterman. A comparison of MO parameters of MOBP derivatives with those of the meso-substituted tetraphenylporphyrin (M(TPP)) and unsubstituted porphine (M(P)) derivatives provides an explanation for the unusual spectral features. The configuration interaction matrix element of the M(OBP) derivatives is found to be the lowest among the known substituted porphyrins, indicating delocalization of ring charge caused by the increase in conjugation of p orbitals of the bromine onto the ring orbitals. The electron-transfer reactivities of the porphyrins have been dramatically altered by the peripheral bromine substituents, producing large anodic shifts in the ring and metal-centered redox potentials. The increase in anodic shift in the reduction potential of M(OBP)s relative to M(TPP)s is found to be large (550 mV) compared to the shift in the oxidation potential (300 mV). These shifts are interpreted in terms of the resonance and inductive interactions of the bromine substituents.

Preparation and characterization of hydrazine derivatives. Part-II: Reaction of transition metal ammonium double sulphates with hydrazine hydrate

Transition metal ammonium double sulphates (NH4)2M(SO4)2· 6H2O, where M = Fe, Co and Ni react with hydrazine hydrate in air giving crystalline compounds of the general formula (N2H5) [M(N2H3COO)3] H2O. The reaction proceeds through (N2H5)2 M(SO4)2, · 3N2H4, (N2H5)2 [M(OH)4 · (N2H4)2], M(N2H3COO)2 · (N2H4)2 and N2H5 [M(N2 H3 COO)3] intermediates. The reaction sequence is followed by chemical analysis and infrared spectra. A possible reaction mechanism has been suggested.

Assignment of Fundamental Vibrations of Hydrazo Derivatives. Carbohydrazide and Diprotonated Carbohydrazide

The Infrared spectra of carbohydrazide, diprotonated carbohydrazide and their deuterated compounds have been measured in the solid state. From the results on thio- and selenocarbohydrazides and other related molecules and normal coordinate analyses using a Urey-Bradley force field assignments of the fundamental vibrational frequencies and a description of the normal modes of carbohydrazide, diprotonated carbohydrazide and their deuterated species are given.