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Bis-thiazole derivatives were synthesised conforming to the Pim1 pharmacophore model following Hantzsch condensation. Pim1 has a major role in regulating the G1/S phase which upon inhibition the cell cycle stops at its early stages. Derivatives 3b and 8b showed the best Pim1 IC50 0.32 and 0.24 µM, respectively relative to staurosporine IC50 0.36 µM. Further confirmation of 3b and 8b Pim1 inhibition was implemented by hindering the T47D cell cycle at G0/G1 and S phases where 3b showed 66.5% cells accumulation at G0/G1 phase while 8b demonstrated 26.5% cells accumulation at the S phase compared to 53.9% and 14.9% of a control group for both phases, respectively. Additional in vivo cytotoxic evaluation of 3b and 8b revealed strong antitumor activity with up-regulation of caspase-3 and down-regulation of VEGF and TNF α immune expression with concomitant elevation of malondialdehyde levels in case of 8b. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor VEGFR-2 has been acknowledged as one of the possible targets for anticancer agents. Considering the pharmacophore features of sorafenib, ten benzenesulfonamide-1,3,4-thiadiazole hybrids 5a–d and 8a–e were synthesized via the cyclization reaction of hydrazine-1-carbodithioate 2 with a bundle of different hydrazonoyl chlorides 3a–d and 6a–e. The preliminary screening of their cytotoxic effect revealed potent inhibition of HepG-2 where 8c and 8e showed the best IC50 of 11.80 and 4.08 μM, respectively, compared to 13.60 μM of staurosporine. Their VEGFR-2 molecular docking simulations illustrated the crucial binding pattern with Glu917, Cys919, Glu885, Asp1046, and Lys868 for kinase inhibition with binding energy −7.90 and 8.40 kcal mol−1, respectively. Moreover, the molecular dynamics simulation of 8c and 8e revealed possible VEGFR-2 binding demonstrating MM-PBSA ΔGbinding, −9.1 and −9.8 kcal mol−1, respectively. Additionally, 8c established 1 to 3 hydrophilic stable H-bonds, while 8e formed 1 to 2 H-bonds throughout the simulation. [ABSTRACT FROM AUTHOR]

Thiazole is a functional group used in cancer treatment modalities in synthetic and natural antitumor medications. In this context, convenient synthesis of new 5-heteroaryl-thiazoles is described via reactions of thiazolylenaminone with sulfanilamide, sulfathiazole, hydrazine hydrate, phenylhydrazine, hydroxylamine, guanidine, aminoazoles, β-dicarbonyl compounds, and diazotized aminoazoles. The constitution of the constructed thiazoles was avowed by elemental analyses and spectral data as well as alternative syntheses wherever possible. Thiazoles were also tested for their antitumor activity toward human cancer cell lines (MCF-7, HCT-116, and HepG-2) and one normal cell line (REP1). Among the synthesized thiazoles, compounds 6, 19, and 23a showed high potent antitumor profiles toward cancer cell lines and found no evidence of human toxicity. [ABSTRACT FROM AUTHOR]

Regio- and stereoselectivity in ene-carbonyl photocycloadditions depended on the spin multiplicity of the excited carbonyl state. The correlation between selectivity and spin state was evaluated by concentration, temperature, and solvent viscosity studies like Paterno-Buchi, determining that weak interaction connected with intersystem crossing can lead to substantial control of regio- and stereoselectivity.

A versatile route to derivatives of [alpha]-amino [beta]-hydroxy carboxylic acids, either with tertiary (from a corresponding glycine equivalent) or a quaternary [alpha]-carbon center is described. The key reaction is the cycloaddition of electronically excited carbonyl compounds (aromatic and aliphatic aldehydes, respectively) to oxazoles. To make the products hydrolytically more labile, a methoxy substituent at position C-5 was introduced leading to the formation of cycloadducts with an orthoester substructure. The photocycloaddition, either with triplet excited (aromatic) carbonyls or with singlet excited (aliphatic) carbonyls, led to the formation of mixtures of endo- and exo-diastereoisomers with moderate to very high exo-selectivities. The 4-unsubstituted 5-methoxyoxazole 1 (glycine equivalent) gave the [2 + 2]-adducts 3a-3f with aldehydes 2a-2f in high yields and excellent diastereoselectivities. Hydrolysis of these compounds resulted in the [alpha]-amino [beta]-hydroxy esters 4a-4f with preferred erythro (S*,S*) configuration. As an extension of this process, 4-alkylated 5-methoxyoxazoles 5a-5f were applied as alkene components and the corresponding cycloadducts with benzaldehyde 6a-6f were obtained. Again, the exo-diastereoisomers were formed as the major products in diastereoselectivities from 73:27 (exo:endo) up to [is greater than]95:5. Hydrolysis of these adducts resulted in the formation of [alpha]amino [beta]-hydroxy esters 7a-7f with like (S*,S*) configuration of the major diastereoisomers. Key words: photo aldol reaction, oxazoles, oxetanes, photocycloaddition, amino acids, hydroxy acids.