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Chemotherapeutic interruption of signaling pathways at receptor tyrosine kinases is an important strategy for attenuating cancer progression. We have synthesized a new generation of polyfunctionalized heterocyclic compounds that bind to an allosteric site in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). The bound compounds induce degradation of the receptor by endocytosis in cancer cells. The Hsp90α chaperone binds to EGFR and is significantly lost during endocytosis, thereby contributing to the reduction of client proteins. Induced EGFR depletion leads to inactivation of downstream signaling due to sequestration of the Bim sensor protein for cytoskeletal proteins, provoking cell detachment from the extracellular matrix and ultimately cancer cell death. The role of glutamine in maintaining the phosphorylation status of EGFR-mediated signaling pathways can be postulated as «no glutamine, no EGFR signaling». Targeted degradation of EGFR is attractive for aiming to attenuate metastatic progression and to override the drug resistance of malignant tumors.

We report here the synthesis of methyl esters of 5-(1H-1,2,4-triazol-3-ylsulfanylmethyl)furan-2-carboxylic acids containing an alkyl or 2(4)-alkoxyphenyl substituent in position 5 of the triazole ring. Alkaline hydrolysis of these esters yielded the corresponding acids. X-ray diffraction studies showed that the oscillating hydrogen atom in the triazole ring of the methyl ester of 5-[5-(2-ethoxyphenyl)-1H-1,2,4-triazol-3-ylsulfanylmethyl] furyl-2-carboxylic acid was located on the N1 atom. The antibacterial properties of the esters and acids were studied.

A series of 2-hydrazino-5-bromomethyl-4,5-dihydrothiazole hydrazones based on substituted N4-allylthiosemicarbazones was synthesized. Some of these hydrazones were found to have moderate antibacterial activity against Staphylococcus aureus 209P, 1 and Shigella flexneri.

A series of substituted 6-alkyl(6H)-3-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines have been synthesized by reaction of 3-alkyl-4-amino-5-thio-1,2,4-triazoles with substituted phenacylbromides in the presence of an equimolar amount of KOH. Mass spectra for the dissociative ionization by electron impact, antibacterial activity, and antitumor properties of the synthesized compounds have been studied. It was established that some compounds at doses of 50 – 100 mg/kg decrease the growth of sarcomas 45 and 37 by 35 – 47%.

The physicochemical properties and antitumor activity of dacarbazine, its analogs, and the new alkylating agent imidazene are reviewed. It is shown that the activity of dacarbazine is superior to most of its analogs. Imidazene exhibits an advantage over dacarbazine with respect to both stability and activity and can be used for the treatment of malignant melanoma and sarcoma of soft tissues and in combined chemotherapy.

The antitumor properties of 2-imidazolinyl-2-hydrazones of acetophenones with various substituents in the benzene ring have been studied. High activity is found for 4-amyloxy-3-nitroacetophenone 2-imidazolinyl-2-hydrazone, which points to the expediency of its further investigation.

Previously, we described the synthesis of phenacylthioimidazolines and investigated the biological properties of the corresponding hydrochlorides. It was found that some hydorchlorides exhibited quite significant sympathicolytic and mutagenic activity. Due to the low solubility of substituted phenacylthioimidazoline hydrobromides in water and the fact that they can cyclize into imidazothiazoles it was difficult to convert the hydrobromides to the corresponding hydrochlorides. For this reason the phenacylthioimidazoline hydrochlorides were synthesized in the present work by reacting the phenacyl chlorides with 2-thio-2-imidazoline. 8 refs., 2 figs., 2 tabs.

Bis(2-chloroethyl)amino derivatives of imidazole, 4(5)-aminoimidazol-5(4)-carboxamide, 4-nitro-5-thioimidazole, benzimidazole, and imidazolylpeptides are reviewed. Data are presented for active compounds, some of which have passed the preclinical testing stage. Structures under consideration are interesting with respect to both the search for new antitumor drugs and the synthesis of compounds with different biological properties.

T h e 1 b e n z y l s u b s t i t u t e d i m i d a z o l e s ( I V g a n d h ) w e r e o b t a i n e d b y t h e a l k y l a t i o n o f t h e i s o d i u m s a l t o f 4 ( 5 ) ( 4 a c e t y l a m i n o p h e n y l ) i m i d a z o l e w i t h b e n z y l c h l o r i d e w i t h s u b s e q u e n t d e a c e t y l a t i o n o f t h e 1 b e n z y l 4 ( 4 a c e t y l a m i n o p h e n y l ) i m i d a z o l e s .