Inga Čikotienė

Co-crystalization and in vitro biological characterization of 5-Aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazole Hsp90 inhibitors

A potential therapeutic strategy for targeting cancer that has gained much interest is the inhibition of the ATP binding and ATPase activity of the molecular chaperone Hsp90. We have determined the structure of the human Hsp90α N-terminal domain in complex with a series of 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles. The structures provide the molecular details for the activity of these inhibitors. One of these inhibitors, ICPD 34, causes a structural change that affects a mobile loop, which adopts a conformation similar to that seen in complexes with ADP, rather than the conformation generally seen with the pyrazole/isoxazole-resorcinol class of inhibitors. Competitive binding to the Hsp90 N-terminal domain was observed in a biochemical assay, and these compounds showed antiproliferative activity and induced apoptosis in the HCT116 human colon cancer cell line. These inhibitors also caused induction of the heat shock response with the upregulation of Hsp72 and Hsp27 protein expression and the depletion of Hsp90 clients, CRAF, ERBB2 and CDK4, thus confirming that antiproliferative activity was through the inhibition of Hsp90. The presence of increased levels of the cleavage product of PARP indicated apoptosis in response to Hsp90 inhibitors. This work provides a framework for the further optimization of thiadiazole inhibitors of Hsp90. Importantly, we demonstrate that the thiadiazole inhibitors display a more limited core set of interactions relative to the clinical trial candidate NVP-AUY922, and consequently may be less susceptible to resistance derived through mutations in Hsp90.

Divergent Pathways and Competitive Mechanisms of Metathesis Reactions between 3-Arylprop-2-ynyl Esters and Aldehydes: An Experimental and Theoretical Study

Mechanistic studies of the reaction between 3-arylprop-2-ynyl esters and aldehydes catalyzed by BF3 ⋅Et2 O were performed by isotopic labeling experiments and quantum chemical calculations. The reactions are shown to proceed by either a classical alkyne-carbonyl metathesis route or an unprecedented addition-rearrangement cascade. Depending on the structure of the starting materials and the reaction conditions, the products of these reactions can be Morita-Baylis-Hillman (MBH) adducts that are unavailable by traditional MBH reactions or E- and Z-α,β-unsaturated ketones. (18) O-Labeling studies suggested the existence of two different reaction pathways to the products. These pathways were further examined by quantum chemical calculations that employed the DFT(wB97XD)/6-311+G(2d,p) method, together with the conductor-like screening model for realistic solvation (COSMO-RS). By using the wB97XD functional, the accuracy of the computed data is estimated to be 1-2 kcal mol(-1) , shown by the careful benchmarking of various DFT functionals against coupled cluster calculations at the CCSD(T)/aug-cc-pVTZ level of theory. Indeed, most of the experimental data were reproduced and explained by theory and it was convincingly shown that the branching point between the two distinct mechanisms is the formation of the first intermediate on the reaction pathway: either the four-membered oxete or the six-membered zwitterion. The deep mechanistic understanding of these reactions opens new synthetic avenues to chemically and biologically important α,β-unsaturated ketones.

Formation of condensed 1H-pyrrol-2-ylphosphonates and 1,2-dihydropyridin-2-ylphosphonates via Kabachnik-Fields reaction of acetylenic aldehydes and subsequent 5-exo-dig or 6-endo-dig cyclizations.

Kabachnik-Fields reactions of various carbocyclic or heterocyclic acetylenic aldehydes together with subsequent Lewis acid catalyzed cyclizations have been studied. It was found that 5-exo-dig versus 6-endo-dig cyclization mode strongly depends on the structure of starting materials. Thus, nonaromatic acetylenic α-anilinomethylphosphonates underwent gold(III)-catalyzed or iodine-mediated 5-exo-dig cyclization to 1H-pyrrol-2-ylphosphonates. In contrast, electron-withdrawing heteroaromatic substrates formed 1,2-dihydropyridin-2-ylphosphonate ring containing materials via an exclusive 6-endo-dig ring-closure process. The dual mode of cyclization is possible only for α-amino (2-alkynylphenyl)methylphosphonates containing a benzene ring.

Rearrangements of propargylic esters can be induced by some electrophiles.

An electrophile-induced rearrangement of propargylic esters without need of transition catalysis is possible. In particular, this observation provides a mild, economic, and effective method for the introduction of benzyl ether derivatives to access functionalized α,β-unsaturated ketones. Preliminary mechanistic studies suggest that this rearrangement undergoes an intramolecular 1,3-acyloxy shift.

Recent advances in the synthesis of benzimidazoles (microreview)

This microreview focuses on the most recent literature (past 3 years) covering new approaches for substituted benzimidazole synthesis.

Synthesis of 4H-thiazines

Thiazines represent an important class of heterocyclic compounds due to their valuable biological properties. For example, some derivatives of thiazine are cannabinoid receptor agonists, also they can act as an antihypotensive, antitubercular, and antibacterial agents. Moreover, thiazine derivatives can be used for gastrointestinal disorders or diabetes prevention. Condensed heterocyclic systems possessing thiazine ring have been reported as antioxidants, analgesic, anti-inflammatory agents, or calcium channel modulators. Also it should be noted that thiazines are useful intermediates in synthetic organic chemistry. How to Cite Urbanaitė, A.; Cikotienė, I. Chem. Heterocycl. Compd. 2016 , 52 , 1. [ Khim. Geterotsikl. Soedin. 2016 , 52 , 1.] For this article in the English edition see DOI 10.1007/s10593-016-1820-z

A facile and efficient synthesis of 1-trichloromethyl-1,2-dihydrobenzo[b][1,6]naphthyridines via three-component reaction among 2-alkynylquinoline-3-carbaldehydes, primary amines, and chloroform

Abstract A three-component reaction among 2-alkynylquinoline-3-carbaldehydes, primary amines, and chloroform leading to novel 1-(trichloromethyl)-1,2-dihydrobenzo[b][1,6]naphthyridines was developed using microwave initiation in an absence of any catalysts. This method provides a facile approach to the title compounds with moderate to higher yields.

Improving the Hsp90 Inhibitors Containing 4-(2,4-Dihydroxyphenyl)-1,2,3- thiadiazole Scaffold: Synthesis, Affinity and Effect on Cancer Cells

BACKGROUND Human Hsp90 chaperone inhibitors are known to be potential anticancer drugs. Previously we have shown a couple of 5-aryl-4-(2,4-dihydroxyphenyl)-1,2,3-thiadiazoles to be promising anticancer agents. OBJECTIVE To improve the compounds containing 4-(2,4-dihydroxyphenyl)-1,2,3-thiadiazole scaffold as human Hsp90 inhibitors. METHOD We employed chemical synthesis to obtain new compounds and assayed their binding to Hsp90 using the fluorescence thermal shift assay and used MTT assays to determine their effect on cancer cells. RESULTS A series of compounds containing the 4-(2,4-dihydroxyphenyl)-1,2,3-thiadiazole scaffold were synthesized as Hsp90 inhibitors. Analysis of their binding to the recombinant N-terminal domain of Hsp90 revealed that four of these compounds bound to Hsp90 with Kd of 0.6 to 0.8 nM. The compounds fully inhibited the growth of all tested cancer cell lines: A549 (lung adenocarcinoma), IGR39 (melanoma), and U87 (glioblastoma), with the effective antiproliferative concentration (EC50) of the compounds reaching 0.35 µM. CONCLUSION This series of 14 novel and efficient Hsp90 inhibitors provided additional information on the structure-activity relationship of Hsp90 inhibitors and may be further developed into drugs targeting Hsp90.