Design, synthesis and antiproliferative evaluation of new tricyclic fused thiazolopyrimidines targeting topoisomerase II: Molecular docking and apoptosis inducing activity.

A novel series of thiazolopyrimidines and fused thiazolopyrimidines was designed and synthesized as topoisomerase II alpha inhibitors. All synthesized compounds were screened by the National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines representing the following cancer types: leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers. Compound 3a was found to be the most potent inhibitor on renal cell line (A-498) causing 83.03% inhibition (IC50 = 1.89 µM). DNA-flow cytometric analysis showed that compound 3a induce cell cycle arrest at G2/M phase leading to cell proliferation inhibition and apoptosis. Moreover, fused thiazolopyrimidines 3a showed potent topoisomerase II inhibitory activity (IC50 = 3.19 µM) when compared with reference compound doxorubicin (IC50 = 2.67 µM). Docking study of all the synthesized compounds showed that compound 3a interacts in a similar pattern to etoposide and stabilizing the topoisomerase cleavage complex (Top2-cc) that accounts for its high potency.

Antimicrobial Activity of Substituted Benzopentathiepin-6-amines.

A number of substituted benzopentathiepin-6-amines and their analogues without a polysulfur ring were synthesized and evaluated in vitro for antimicrobial activity against a panel of reference bacterial and fungal strains. Trifluoroacetamide 14 demonstrated high antibacterial activity against Staphylococcus aureus (MRSA strain) with a MIC of 4 µg/mL, which was four-fold higher than the activity of a reference drug amoxicillin. This compound was also most active against the Candida albicans fungus (MIC of 1 µg ml-1), whereas amide 17 containing a morpholine substituent was most active against the Cryptococcus neoformans fungus (MIC of 2 µg ml-1). These compounds have no hemolytic activity and are low cytotoxic. Replacement of the pentathiepine ring with 1,3-dithiolan-2-one or 1,3-dithiolane moieties leads to loss of antimicrobial activity. Based on the QSAR analysis and molecular docking data, bacterial DNA ligase might be one of the targets for the antibacterial activity of substituted benzopentathiepin-6-amines against S. aureus.

The influence of some promising fused azaisocytosine-containing congeners on zebrafish (Danio rerio) embryos/larvae and their antihaemolytic, antitumour and antiviral activities.

The present study was aimed at broadening the profile of toxicity and biological activity of promising fused azaisocytosine-containing congeners (I-VI) possessing medical applicability and important pharmacokinetic properties. For this purpose, the in vivo zebrafish test was applied for evaluating embryotoxic effects of test compounds, whereas the ex vivo model of oxidatively-stressed rat erythrocytes was developed for assessing their antihaemolytic activities. Additionally, the MTT-based assays suitable for assessing cytotoxic and antiviral activities of I-VI were employed. The influence of compounds I-VI on zebrafish embryos/larvae was carefully investigated in relation to lack or presence of various substituents at the phenyl moiety. The least embryotoxic proved to be the parent compound (I) and its para-methyl (II) and ortho-chloro (III) derivatives. Simultaneously, they revealed the minimum embryotoxic concentrations higher than that of aciclovir, what makes them safer than this pharmaceutic. Moreover, most of test compounds showed protective effects (better or comparable to that of ascorbic acid) on oxidatively-stressed erythrocytes. All the investigated compounds were effective at inhibiting the growth of human solid tumours of pharynx (FaDu) and tongue (SCC-25). The majority of molecules showed good selectivity indices. The most selective proved to be II showing in normal Vero cells over a 5-fold and an almost 3-fold decreased cytotoxicity relative to that in tumour SCC-25 and FaDu cells, respectively. Additionally, a 3,4-dichloro derivative (VI) was shown to possess concentration-dependent inhibitory effects on the replication of Herpes simplex virus type 1 and simultaneously at active concentrations was found to be nontoxic for normal Vero cells.

Design of New Benzo[h]chromene Derivatives: Antitumor Activities and Structure-Activity Relationships of the 2,3-Positions and Fused Rings at the 2,3-Positions.

A series of novel 4H-benzo[h]chromenes 4, 6-11, 13, 14; 7H-benzo[h]chromeno[2,3-d]pyrimidines 15-18, 20, and 14H-benzo[h]chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 19a-e, 24 was prepared. The structures of the synthesized compounds were characterized on the basis of their spectral data. Some of the target compounds were examined for their antiproliferative activity against three cell lines; breast carcinoma (MCF-7), human colon carcinoma (HCT-116) and hepatocellular carcinoma (HepG-2). The cytotoxic behavior has been tested using MTT assay and the inhibitory activity was referenced to three standard anticancer drugs: vinblastine, colchicine and doxorubicin. The bioassays demonstrated that some of the new compounds exerted remarkable inhibitory effects as compared to the standard drugs on the growth of the three tested human tumor cell lines. The structure-activity relationships (SAR) study highlights that the antitumor activity of the target compounds was significantly affected by the lipophilicity of the substituent at 2- or 3- and fused rings at the 2,3-positions.

Three-Component, Diastereoselective Prins-Ritter Reaction for cis-Fused 4-Amidotetrahydropyrans toward a Precursor for Possible Neuronal Receptor Ligands.

Here, we report an unprecedented, highly diastereoselective Prins-Ritter reaction of aldehydes, homoallylic alcohols, and nitriles in a three-component coupling reaction for the synthesis of tetra-cis-substituted 4-amidotetrahydropyrans. In this study, the reaction was not only applied for carbohydrate-based heterobicycles but also for more complex heterotricycles, showing acceptable levels of conversion yield (42-97% BRSM) and exclusive diastereoselectivity. Furthermore, the latter heterotricycles were converted to nine analogues of our neuronal receptor ligands IKM-159 and MC-27. An in vivo assay by intracerebroventricular injection in mice suggested that the substituent at C9 of the novel analogues interferes with the molecular interactions with the AMPA receptor, which was originally observed in the complex of IKM-159 and the GluA2 ligand binding domain. Our research has thus shown the power of a multicomponent coupling reaction for the preparation of a structurally diverse compound collection to study structure-activity relationships of biologically active small molecules.