Novel purine derivatives as selective CDK2 inhibitors with potential anticancer activities: Design, synthesis and biological evaluation.

Purine analogues were discovered to be inhibitors of CDK2, suggesting a potential therapeutic scaffold. This paper addresses the design, synthesis, and anticancer evaluation of purine analogues as kinase inhibitors. In the early stages of the investigation, the designed compounds demonstrated a promising docking score and greater protein-ligand stability in MD simulation than the standard, indicating a higher affinity against CDK2. Thus, we synthesised new purine analogues under simple and optimised reaction conditions. Among the studies under NCI-60, 5g and 5i were the most effective, with a percentage GI of 98.09 and 90 against OVCAR-4 and SNB-75, respectively, at a dose of 10 µM. Additionally, 5g and 5i demonstrated 7.80-fold and 1.54-fold greater cytotoxicity against PA-1 and MCF-7, with IC50s of 1.08 µM and 3.54 µM, respectively, compared to seliciclib (8.43 µM and 5.46 µM). In addition, 5g and 5i showed selective cytotoxicity against PA-1 and MCF-7 than normal cells, with selectivity indexes of 26.40 and 15.45, respectively, as compared to the standard (SI=3.83 and 5.91). In the kinase selectivity assay, both compounds demonstrated greater affinity against CDK2 than other kinases, with IC50 of 0.21 µM and 0.59 µM, in contrast to the standard (IC50 = 0.63 µM). Furthermore, 5g confirmed kinase inhibition in the western blot by lowering CDK2, cyclin A2, and other downstream substrates. Moreover, it triggered cell death by apoptosis and cell cycle arrest in G2/M. Taken together, 5g merits further investigation in PKPD research to discover a potential therapeutic candidate against cancer.

Facile Green Synthesis of Iron Oxide Nanoparticles and Their Impact on Cytotoxicity, Antioxidative Properties and Bactericidal Activity.

Background: Bioreductive processes are quite potent, effective and affordable for the synthesis of green nanoparticles (NPs), as compared to the physical and chemical methods. The present study aimed to evaluate the bactericidal, antioxidative and anticancer activity of turmeric rhizome-iron oxide nanoparticles (FeONPs) derived from the turmeric rhizome (Curcuma amada) using ferric chloride as a precursor. Methods: With focusing on the manufacture of FeONPs via green approach, we characterized the NPs using FTIR, FT-Vis, DLS, and UV-Vis spectroscopy. The produced particles were tested for antibacterial, antioxidant, and anticancer properties. The synthesized NPs were also examined using the MDA-MB-231 human epithelial breast cancer cell line and NCI-60 cancer cell lines. Results: The antioxidant activity of TR-FeONPs was concentration-dependent. The scavenging activity of TR-FeONPs was 76.09% at a concentration of 140 µg/ml. Using different concentrations of TR-FeONPs in the MTT assay against the MDA-MB-231 cell line indicated a reduction of less than 50% in cell viability at 125 µg/ml. Moreover, TR-FeONPs exhibited an effective bactericidal property. The gTR-FeONPs synthesized bioreductively were found to be effective in renal cancer, UO-31 cell line, with GI50 value of 66.64%. Conclusion: Our study showcases a sustainable method based on green chemistry principles to produce FeONPs utilizing turmeric rhizome. We anticipate that the FeONPs produced through this biosynthesis process could serve as a promising drug delivery system in cancer treatment and as an effective antimicrobial agent against various diseases.

PI3Kδ and mTOR dual inhibitors: Design, synthesis and anticancer evaluation of 3-substituted aminomethylquinoline analogues.

Phosphatidylinositide-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) have recently been identified as potential cancer targets. In our work, a new family of quinoline analogues was designed, developed, and evaluated as dual inhibitors of PI3Kδ/mTOR. The preliminary biological activity analysis led to the discovery of the lead compounds 5h and 5e. Compounds 5h and 5e exhibited excellent anti-tumor potency with IC50 of 0.26 µM and 0.34 µM against Ramos cells, respectively. Importantly, based on the enzymatic activity assay results, compounds 5h and 5e were identified as dual inhibitors of PI3Kδ and mTOR, with IC50 values of 0.042 µM and 0.056 µM for PI3Kδ and 0.059 µM and 0.073 µM for mTOR, respectively. Furthermore, these compounds showed superior selectivity for blocking PI3Kδ compared to other PI3K isoforms (α, ß, and γ), supporting the concept of developing inhibitors that specifically target PI3Kδ/mTOR. The most effective compound 5h was chosen for additional biological testing. At a low dose of 0.5 µM, a western blot investigation confirmed the anticancer effects by inhibiting the PAM cascade, which in turn reduced downstream biomarkers pAkt (Ser473), pAkt (Thr308), and pRPS6 (Ser235/236). Furthermore, it increased apoptosis at the early (10.03 times) and late (17.95 times) stages in the Annexin-V assay as compared to the standard. In addition, the expression of p53, caspase-3, caspase-9, and the Bax/BCl-2 ratio were all significantly increased by compound 5h in the ELISA assay. Based on these results, it appears that 5h may activate the intrinsic apoptosis pathway, which in turn triggers cell death. Furthermore, the anticancer effects could be attributed to the inhibition of PI3Kδ/mTOR, as shown by docking interactions. Lastly, it demonstrated improved in vitro metabolic stability and passed the in silico ADMET/drug-likeness test. This profile recommends 5h for future in vivo PK-PD and efficacy investigations in animal cancer models.

Recent Studies on Serotonin 5-HT2A Receptor Antagonists in Medicinal Chemistry: A Last Decades Survey.

In the last decades, much attention has been paid to the functioning of receptors to understand better how they work with various chemical motifs. Among different families, G-proteincoupled receptor (GPCR) families have drawn much attention in the twenty-first century. They are the most prominent signal transducer across the cell membrane, comprising thousand-odd proteins. One of the members of GPCRs is the serotonin 2A (5-HT2A) receptor, which has been associated with complex etiological mental illnesses. In this survey, we collected data on 5-HT2A, i.e., the role of 5- HT2A receptors in human and animal analogy, various binding site functionalities, advanced effects, and synthetic aspects.

Regioselective synthesis of triazolo[3,4-e]purine derivatives and their anti-cancer activity against NCI-60 cell-lines.

INTRODUCTION: Due to the vast medicinal importance of purine nucleoside, a hybrid molecule of triazole with purine ring might explode a lead molecule in the pharma sector and based on the last decade's studies suggested that the nitrogen-rich molecules possess a wide range of medicinal importance. AIM: Due to the vast application of purine nucleoside itself in the field of cancer research, we synthesized triazolo[3,4-e]purines and screened them for their anti-cancer study against NCI-60 cell lines by the protocol used by NIH. MATERIALS AND METHODS: The targeted molecules, 4-chloro-5a,6-dihydro-8-substitutedphenyl-1H-[1,2,4]triazolo[3,4-e]purine derivatives (4a-4h) were synthesized in a two-step procedure by nucleophilic substitution (SN) at C-2 chlorine followed by formation of the triazole ring by acid-catalyzed reaction in the polar protic solvent. RESULTS: It was observed that the regioselective approach followed in C-2 chlorine replacement instead of C-6 chlorine during SN reaction. One-dose response of selected three molecules (4a, 4b, and 4c) showed that 4b (K-562: 64.47 µM & SR: 63.38 µM; mean GI50: 99.09 µM) was found to be more potent than 4a and 4c. CONCLUSIONS: We have described in this study the general synthetic method for triazolo[3,4-e]purines as an innovative class of potential anticancer agents. The dose-response curve in the sense of mean GI50 for three compounds across all 60 cell lines, 4b can be served as lead after necessary modification.

Microwave and Conventional Study of Coumarin-Oxadiazole Adducts and their Anti-Microbial Evaluation.

INTRODUCTION: Nowadays, researchers are progressively concentrated to generate economical, affordable and also greener synthesis approach for the synthesis of various heterocycles. On look at the beauty of coumarin molecules and oxazoles, it seems to be lead  molecules in the anti-microbial area. AIM: With the target to identify efficient molecules, we studied 2-oxo-2H-chromen-4-yl-2-((5-substituted aryl-1,3,4-oxadiazol-2-yl) thio)acetate derivatives using two synthetic protocol/methods, i.e. conventional synthesis and microwave-based synthesis. MATERIALS AND METHODS: Two simultaneous methods, i.e. conventional and microwave synthesis have been used for the synthe-sis of 2-oxo-2H-chromen-4-yl-2-((5-substituted aryl-1,3,4-oxadiazol-2-yl)thio)acetate (6a-l) derivatives. The desired molecules were synthesized by conventional and microwave synthesis and a comparative study was carried out to identify an easy route for industrial applications. The confirmations of the compounds were carried out by spectroscopic techniques such as IR, 1H NMR, 13C NMR, mass spectra and elemental analysis. RESULTS: All synthesized compounds were evaluated for their in-vitro antibacterial activity against gram-positive bacteria (Staphylococcus aureus, Staphylococcus pyogenes), gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), and antifungal activity (Candida albicans, Aspergillus niger). CONCLUSIONS: All conventional synthesis of final coumarin derivatives were completed within 4-6 h. While that of microwave-based reaction took comparatively more reaction time. Surprisingly, the compounds 6f and 6g could not be synthesized by microwave radiation even after 32 minutes of irradiation. As to the medicinal application part, microbial evaluation of synthesized analogues showed that the compounds 6b, 6e, 6d, and 6j were found more potent in comparison to the reference drug.

Synthesis of Azide Functionalized Tetrahydrobenzofurans and their Antineoplastic Study.

BACKGROUND: In chemistry, the derivatives of benzofuran which are substituted on five-membered ring constitute one of the salient moieties in medicinal field and a survey of literature revealed that a good number of reports have shown that tetrahydrobenzofuran derivatives are of valuable biological activities. AIM: On the basis of previous survey, we aimed to generate a series of 2-(4-azidobenzoyl)-3-substitutedaryl-6,6-dimethyl-2,3,6,7-tetrahydrobenzofuran-4(. MATERIALS AND METHODS: The tetrahydrobenzofuran derivatives were synthesized by multi-component reactions. It was achieved by coupling of dimedone (3.57 mmole), 4-azido phenacyl bromide (3.92 mmole) and various aromatic aldehydes (3.57 mmole) using two different bases i.e. pyridine and. RESULTS: The results from anti-cancer study shows that the compound 4a exhibited diverse cytotoxic activity against renal cancer panel (UO-31) with significant selectivity and had inhibitory effect on the generation of UO-31 (growth percent= 69.36%) and the compound 4e showed comparable activity in the same cell-line (UO-31: growth percent= 80.86%). CONCLUSIONS: In summary, a series of azide group containing tetrahydrobenzofuran derivatives have been synthesized and were evaluated for their anticancer activity. It was concluded that the derivatives 4a and 4e exhibited promising anticancer activity. Nature of substituent on phenyl ring seems to be the crucial factor affecting the activity in both the compounds.

In Silico and in Vitro Studies of Fluorinated Chroman-2-Carboxilic Acid Derivatives as an Anti-tubercular Agent.

BACKGROUND: Despite the use of traditional method, Ugi reaction currently is a well-established multicomponent reaction. Chromane motif itself possesses a variety of biological functions. In order to improve its anti-tubercular activity, it is necessary to modify it accordingly. AIM: To ensure relation between in silico and in vitro study, we have carried out in vitro screening against H37Rv anti-tubercular agent. MATERIALS AND METHODS: Ugi four-component condensation (U-4CCRs) between 6-fluorochroman-2-carboxylic acid, various aryl aldehyde, 3,4,5-trimethoxy amine and tert-butyl isocyanide, gave N-((tert-butylcarbamoyl)(4-substitutedphenyl) methyl)-6-fluoro-N-(3,4,5-trimethoxyphenyl) chroman-2-carboxamide. The molecular level insight of all compounds was carried out by molecular docking study against the receptor tyrosine phosphatase PtpB. All these newly synthesized compounds were screened for their anti-microbial activity against Mycobacterium tuberculosis H37Rv to determine the MIC, IC50 and IC90 of the compound. RESULTS: The compound 5d also shows large hydrophobic surface contact on the face of the α7-α8 (Ile 207, Phe 211, Met 206, Ile203, Phe161, Phe80, Met126, Tyr130, Val231 and Leu101) that lines one side of the entrance to the active site of the receptor. The compound 5d bind with tyrosine phosphatase PtpB with predicted docking geometric score of 4664, whereas a score of rifampicin was 6586 determined. CONCLUSION: From the docking studies, compound 5d, was considered to be the potent inhibitor, which gave strong supportive coordinate with the in vitro study. It is highly active against H37Rv, having MIC and IC50 value of was 70 µM and 53 µM respectively in in vitro study.

Dihedral angle study in Hesperidin using NMR Spectroscopy.

Hesperidin is flavonoid molecule found in citrus fruits (Citrus reticulata), especially difficult to extract, classify and characterize. Present work is to study the unresolved relative configuration of Hesperidin through the dihedral angle, coupling constant and different NMR techniques. The Karplus equation and its modifications have been originated from the valence bond theory and associated with dihedral angle and coupling constant. The result data set of calculated dihedral angle can probe significant method to assign the virtual configuration of natural products and also resolved stereochemistry of Hesperidin at C-2 position in. Copyright © 2016 John Wiley & Sons, Ltd.