Medicinal Chemistry

The janus kinases (JAKs) comprise an important class of non-receptor protein tyrosine kinases. Cytokine and receptor binding can cause the activation of JAKs, and then activate the "signal transcripts and transcriptional activator”, making JAK enter the nucleus to induce target gene expression. JAKs regulate inflammatory diseases, bone marrow hyperplasia and a variety of malignant tumours. Using JAKs inhibitors as the therapy for organ transplantation and immune disease has a very important significance. In recent years, many of the JAKs inhibitors have been developed one after another. Pan JAKs inhibitor and selective JAK2 or JAK3 inhibitor research progress are reviewed in this article

Three novel imidazole[4,5-f][1,10]phenanthroline-based oxovanadium complexes [VO(hntdtsc)(HPIP)] (1) (hntdtsc = 2-hydroxyl-1-naphthaldehyde thiosemicarbazone, HPIP = 2-(2-hydroxylphenyl)imidazole[4,5-f][1,10]phenanthroline), [VO(hntdtsc)(m-HPIP)] (2) (m-HPIP = 2-(3-hydroxylphenyl)imidazole[4,5-f][1,10]phenanthroline), [VO(hntdtsc)(p-HPIP) (3) (p-HPIP = 2-(4-hydroxylphenyl)imidazole[4,5-f][1,10]phenanthroline), have been synthesized and characterized by elemental analyses and spectroscopic techniques. Their DNA-binding properties with calf-thymus DNA (CT-DNA) were studied by various methods. The cytotoxicity of these three complexes was evaluated by 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The electronic spectral results reveal that three complexes can bind to CT-DNA by intercalation mode. The electrophoresis studies also show that they can efficiently cleave pBR322 DNA. The in vitro antiproliferative activity of complex 1 against human CaSki, SiHa, K562, HepG2, EC9706 and EC109 cell lines is proved to be more effective than both 2 and 3.

Molecular docking studies were performed on 144 newly designed isatin analogs by using Glide v 5. 0 on the active site of five crystal structures of EGFR enzymes (PDB ID 2J5F, 2ITW, 2ITY , 2ITX and1M17) to study the binding mode of these analogs. Binding mode analysis of the compounds with the highest docking scores (-8. 31, -5. 90, -7. 16, -6. 395 and -8. 14) was carried out and were compared with that of the co crystallized ligands DJK_3021_A, AFN941, irressa, AMP-PNP and AQ4 in the active sites of 2J5F, 2ITW, 2ITY, 2ITX and 1M17 respectively. ADME properties of all the newly designed isatin analogs 1-144 was calculated by Qik Prop v3. 0. All the designed compounds were found to exhibit lead like properties from the calculated ADME properties.

The aim of this study was to investigate the correlation of serum folate concentration in newly diagnosed patients with colorectal cancer. Patient population consisted of 101 sporadic colon cases, newly diagnosed, non-alcoholic and non-multivitamins users. Control population consisted of 130 healthy subjects. Venous blood was collected prior to the first chemotherapy intervention. Folate, vitamin B12 and homocysteine were measured using an automated analyzer system. Vitamin B6 was quantified using an enzyme immunoassay. Insulin and leptin were measured using immunoradiometric assay. Folic acid and vitamin B12 were significantly increased in cases compared to controls (15 ± 7 ng/ml vs. 10 ± 4 ng/ml, P=0.01; 330 ± 200 pg/ml vs. 220 ± 100 pg/ml, P=0.02) respectively. Folic acid and BMI were inversely correlated in controls (r=-0.32; P=0.05). There was no significant difference of homocysteine and vitamin B6 between cases and controls. Leptin and insulin were significantly higher in cases with BMI ≥ 27 than in controls with BMI ≥ 27 (16 ± 7 ng/ml vs. 14 ± 7 ng/ml; 32 ± 18 μIU/ml vs. 29 ± 11 μIU/ml). However, stratifying leptin and insulin by cancer stages yielded to no clear pattern. Folate may be implicated as a potential aetiological factor for colorectal cancer.

Aim: To design and synthesize a series of novel 7-hydroxy-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxylate derivatives and evaluate their anti-HIV-1 activities. Methods: Holding the same triad of metal-chelating heteroatoms for the catalytic site of IN and introducing a new hydroxyl group into the adjacent position of the amide to form another three-heteroatoms group for metal chelation, a series of novel 7-hydroxy-1,3-dioxo-2,3-dihydro-1Hpyrrolo[ 3,4-c]pyridine-4-carboxylate derivatives were designed and synthesized through multi-step chemical reactions. All the synthesized compounds were evaluated for their inhibitory activities against HIV-1 replication. Results: Thirtyfive new compounds (5–13) have been designed, synthesized and bioassayed. Their structural features were determined by 1H-NMR spectra, and low- and high-resolution mass spectra. Most of the synthesized compounds showed moderate to potent activities against HIV-1. Among the analogs, compounds 7d, 7f, 7i-7j, 8d and 9c exhibited potent anti-HIV-1 activities (EC50<10 μM). In particular, 7d exhibited significant anti-HIV-1 activities with EC50 values of 1.65 μM. Conclusion: This study provides a new template for further development of potent anti-HIV-1 drugs, and the preliminary SAR among the newly synthesized analogs provided useful indications for guiding further rational design of potent anti-HIV-1 agents.

The phebalosin was isolated from hexane extract of the Polygala paniculata (Polygalaceae). The structural modifications of phebalosin were performed on the epoxy group with different nucleophiles such as H2O, ethoxy, methoxy, isopropoxy and n-butoxy for the corresponding derivatives and with acetic   fungus Paracoccidioides brasiliensis. In this work phebalosin showed promised antifungal activity against isolates of P. brasiliensis with MIC value of 31.2 and 62.5 μg/ml. The compound 3 presented the better activity with MIC value of 1.9 μg/ml gainst the isolate P. brasiliensis Pb03. Besides, it was used methods of theoretical Chemistry, and chemometrics analysis techniques to perform a SAR study. The compounds activity is due to both types of properties – electronic and structural ones. Overall, these data open new possibilities for the potential use of phebalosin and its structural modifications as antifungal.

Turmeric (Curcuma longa) is widely used popular Indian medicinal plant which belongs to the family of Zingiberaceae. Indian turmeric is preferred due to its high Curcumin content as compared to other countries. Curcuminis small molecular weight polyphenolic compound and lipophillic in nature. This active constituent of turmeric is isolated from curcuma longa and it provides colour to turmeric. Curcumin has various medicinal properties and shows Antiinflammatory, anti-oxidant, anti-bacterial and anticancer activities. It has been observed that the chemical composition of most of the herbs changes with geographical region which may be due to climatic conditions and biochemical variations. The present work deals with phytochemical investigation of the turmeric rhizomes obtained from Bhandara District and determination of its curcumin content. Curcumin was isolated from turmeric rhizomes using reported method. The isolated curcumin was characterised by UV, FTIR and TLC methods. The curcumin content of turmeric rhizomes obtained from Bhandara District was determined and compared with other samples collected from different geographical regions. It was concluded that turmeric rhizomes obtained from Bhandara region has highest curcumin content as compare to other regions in Maharashtra (India).

Natural products, which reduce hyperglycemia by enhancing the glucose uptake in peripheral tissues, have been considered to be effective for treatment of Type-2 Diabetes Mellitus. Salvia miltiorrhiza (Labiatae), danshen, has been widely used traditional Chinese medicine for the treatment of various cardiovascular and cerebrovascular diseases. In the present study, different extracts of Salvia miltiorrhiza root were investigated for their ability to enhance glucose uptake in differentiated 3T3-L1 adipocytes. An in vitro bioassay guided fractionation approach was adapted to isolate the active principle of Salvia miltiorrhiza using extensive column chromatographic techniques. The structure of active compound was elucidated using various spectroscopic methods (ESI-MS, MALDI-ToF, 1H-NMR, 13C-NMR, COSY, TOCSY, HETCOR) and determined to be magnesium salt of salvianolic acid B (SAB). SAB showed concentration dependent increase in glucose uptake in 3T3-L1 adipocytes. The efficacy of the active principle was also evaluated for its antidiabetic activity in streptozotocin-induced diabetic rats. SAB (25 mg/kg) significantly improved the glucose tolerance in diabetic rats (*p<0.05, ** p<0.01). The SAB treatment group showed significantly lower (*p<0.05) blood glucose levels over 120 min as compared to diabetic control group. Thus, these results suggested that SAB has the potential to be developed as a potential glucose-lowering agent by increasing glucose uptake in peripheral tissues in the treatment of diabetes mellitus.