Identification of thienopyrimidine derivatives tethered with sulfonamide and other moieties as carbonic anhydrase inhibitors: Design, synthesis and anti-proliferative activity.

Eighteen novel compounds harboring the privileged thienopyrimidine scaffold (5a-q, and 6a),were designed based on molecular hybridization strategy. These compounds were synthesized and tested for their inhibitory activity against four different carbonic anhydrase isoforms: CA I, II, IX, and XII. Microwave and conventional techniques were applied for their synthesis. Compounds 5b, 5g, 5l, and 5p showed the highest inhibition activity against the four CA isoforms. Compound 5p exhibited promising inhibitory activity against CA II, CA IX and CA XII with KI values of8.6, 13.8, and 19 nM, respectively, relative to AAZ, where KIs = 12, 25, and 5.7 nM, respectively. Also, compound 5 l showed significant activity against the tumor-associated isoform CA IX with KI = 16.1 nM. All the newly synthesized compounds were also screened for their anticancer activity against NCI 60 cancer cell lines at a 10 µM concentration. Compound 5n showed 80.38, 83.95, and 87.39 % growth inhibition against the leukemic cell lines CCRF-CEM, HL-60 (TB), and RPMI-8226, respectively. Also, 5 h showed 87.57 % growth inhibition against breast cancer cell line MDA-MB-468; and 66.58 and 60.95 % inhibitionagainst renal cancer cell lines UO-31, and ACHN, respectively. A molecular docking studywas carried out to predict binding modes of our synthesized compounds in the binding pockets of the four carbonic anhydrase isoforms, and results revealed that compounds 5b, 5g, 5l, and 5p succeeded in mimicking the binding mode of AAZ through metal coordination with Zn+2 ion and binding to the amino acids Thr199, His94, and His96 that are critical for activity.

Identification of novel furo[2,3-d]pyrimidine based chalcones as potent anti-breast cancer agents: synthesis, in vitro and in vivo biological evaluation.

Various substituted synthetic chalcones demonstrated potent anti-cancer activities. In the current study a series of novel furo[2,3-d]pyrimidine based chalcones were synthesized as potential anticancer agents. Among the different substituted derivatives, two of the halogen bearing chalcones, 5d and 5e, demonstrated potent anti-proliferative activity against an NCI 59 cell line, with mean GI50 values of 2.41 µM and 1.23 µM, respectively. Moreover, both compounds showed pronounced cytotoxic activity (5d; 1.20 ± 0.21, 5e; 1.90 ± 0.32) against the resistant MCF-7 cell line when compared to doxorubicin; 3.30 ± 0.18. Such outcomes provoked the initiation of an in vivo anticancer assessment study, where compound 5e revealed comparable results to doxorubicin.

One-Pot Synthesis of Novel Thiazoles as Potential Anti-Cancer Agents.

BACKGROUND: Thiazole and thiosemicarbazone derivatives are known to have potential anticancer activity with a mechanism of action related to inhibition of matrix metallo-proteinases, kinases and anti-apoptotic BCL2 family proteins. MATERIALS AND METHODS: A novel three series of 5-(1-(2-(thiazol-2-yl)hydrazono)ethyl)thiazole derivatives were prepared in a one-pot three-component reaction using 2-(2-benzylidene hydrazinyl)-4-methylthiazole as a starting precursor. MS, IR, 1H-NMR and 13C-NMR were used to elucidate the structures of the synthesized compounds. Most of the synthesized products were evaluated for their in vitro anticancer screening against HCT-116, HT-29 and HepG2 using the MTT colorimetric assay. RESULTS: The results indicated that compounds 4c, 4d and 8c showed growth inhibition activity against HCT-116 with IC50 values of 3.80 ± 0.80, 3.65 ± 0.90 and 3.16 ± 0.90 µM, respectively, compared to harmine (IC50 = 2.40 ± 0.12 µM) and cisplatin (IC50 = 5.18 ± 0.94 µM) reference drugs. Also, compounds 8c, 4d and 4c showed promising IC50 values of 3.47 ± 0.79, 4.13 ± 0.51 and 7.24 ± 0.62 µM, respectively, against the more resistant human colorectal cancer (HT-29) cell line compared with harmine (IC50 = 4.59 ± 0.67 µM) and cisplatin (IC50 = 11.68 ± 1.54 µM). On the other hand, compounds 4d, 4c, 8c and 11c were the most active (IC50 values of 2.31± 0.43, 2.94 ± 0.62, 4.57 ± 0.85 and 9.86 ± 0.78 µM, respectively) against the hepatocellular carcinoma (HepG2) cell line compared with harmine (IC50 = 2.54 ± 0.82 µM) and cisplatin (IC50 = 41 ± 0.63 µM). The study also suggested that the mechanism of the anticancer action exerted by the most active compounds (4c, 4d and 8c) inside HCT-116 cells was apoptosis through the Bcl-2 family. CONCLUSION: Thiazole scaffolds 4c, 4d and 8c showed anticancer activities in the micromolar range and are appropriate as a candidate for cancer treatment.

Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer.

Phosphoinositol-3-kinase enzyme (PI3K) plays a crucial role in driving oncogenic growth in various mammalian cells, particularly pancreatic cells. In the current study a series of novel furo[2,3-d]pyrimidine based-compounds were designed and synthesized as potential PI3K-α inhibitors. In accordance to the structure-activity relationship (SAR) studies of known PI3K-α inhibitors, different linkers including amide, urea and ether were attached to a piperazinyl furo[2,3-d]pyrimidine core. The synthesized compounds that revealed moderate PI3K-α inhibitory activity were tested for their anti-proliferative activities against pancreatic carcinoma on the PANC-1 cell line. Compounds 7b and 8a showed the highest anti-proliferative activity with IC50 values of 4.5 µM and 6 µM, respectively and relatively, the best in vitro PI3K inhibition ability within the newly synthesized compounds. Additionally, all the newly synthesized final compounds were tested on 60 human cancer cell lines. A docking study was carried out on the PI3K-α active site showing a comparable binding mode to that of FDA approved PI3K-α inhibitors. These newly discovered lipid kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agents.

Synthesis Under Microwave Irradiation and Molecular Docking of Some Novel Bioactive Thiadiazoles.

BACKGROUND: A novel series of fused imidazole was prepared from the reaction of 2- bromoacetyl-3-phenyl-1,3,4-thiadiazole with various heterocyclic amines under microwave irradiation. The structures of all the novel products were elucidated based on the elemental analysis and spectral data. RESULTS: In addition, the biological activity of the newly synthesized compounds was evaluated and the results obtained indicate their potency as anti-inflammatory, analgesic and anti- ulcer agents. CONCLUSION: The binding mechanism of the most active compounds was studied using MOE to analyze the molecular interactions.

Synthesis and Antitumor Activity of Novel [1,2,4,5]-tetrazepino[6,7-b] indole Derivatives: Marine Natural Product Hyrtioreticuline C and D Analogues.

BACKGROUND: Several biologically active indole alkaloids have been isolated from marine organisms over the previous few years. Many scientsts interested in synthesis of the marine azepinoindole alkaloids due to their wide range of bioliogical activies. OBJECTIVE: We interested herein to synthesize a new series of some analogues of new naturally occurring azepinoindole alkaloids. METHOD: A novel series of [1,2,4,5]tetrazepino[6,7-b]indoles, Marine natural product Hyrtioreticuline C and D analogues, were synthesized via the reaction of 3-hydrazonoindolin-2-one with hydrzaonoyl chlorides in basic medium. RESULTS: The spectral data of the products proved their structure. All new derivatives were tested against two carcinoma cell lines ((A-549 & HepG2)) in comparison with the well-known anticancer standard drug (cisplatin) and two derivatives from the tested compounds showed activity more potent than the reference drug. CONCLUSION: We succeeded in synthesis of new antitumor active azepinoindole alkaloids.

New fused pyrimidines of potential biosignificant interest. Syntheses and molecular modelling studies.

New derivatives of thieno[3,2-d]pyrimidine and thieno[2,3-b]pyrrole 5a,b and 6a,b, respectively, were obtained from the corresponding thiophene-2-carboxamides 4a,b. On the basis of compounds 5b, 6a and 6b, two novel series of tricyclic- and tetracyclic-condensed pyrimidines 8-15 and 16-19, respectively, were synthesized by the application of the cyclization reactions of 5b and 6a,b with a variety of commercially available reactants. Geometry optimization of selected structures, using the AM1 semiemperical method, revealed a smaller ionization potential and a lower degree of conformational freedom for the tetracyclic pyrimidine derivatives relative to their tricyclic counterparts. Interestingly, computation of the solvation free energies of the lowest energy conformers at physiological conditions indicated that the series is highly soluble under these conditions. The trend in solubility as implied by the relative magnitudes of the solvation free energies is suggestive of a greater contribution of higher moments of charge distribution in modulating the interaction of the structures with the biological environment which could be detrimental for the binding modes of these structures to their putative receptor sites.

Unlocking the chemotherapeutic potential of beta-aminovinyl ketones and related compounds.

The role of beta-aminovinyl ketones as synthetic intermediates has been well categorised, but recent developments have shown an interesting array of applications and new chemotherapeutic potential, both in the preparation of biologically active heterocycles and as pharmacophores in their own right.Medicinal chemists are accustomed to using the products of Knoevenagel-type condensations as auxiliaries for the synthesis of N-containing heteroaromatic compounds. One such example of these chemical building blocks are beta-aminovinyl ketones-valuable synthetic intermediates that have been used in the preparation of pyridines, pyrimidines, pyrazoles, and many other heterocyclic motifs. This review highlights their recent use in the synthesis of biologically active targets as part of drug discovery programmes and in natural product synthesis. However, it is becoming increasingly evident that the enaminone motif may serve as a therapeutic pharmacophore in its own right. This review highlights the range of biological responses that beta-aminovinyl ketones elicit, including as antitumour, antibacterial, and anticonvulsant agents. Thus, with a broad spectrum of biological properties and as versatile chemical intermediates, it is clear that beta-aminovinyl ketones offer great potential in the search for new chemotherapeutic agents.