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11.
Gangjee A Zaware N Raghavan S Yang J Thorpe JE Ihnat MA 《Bioorganic & medicinal chemistry》2012,20(7):2444-2454
With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRβ and VEGFR-2 we designed and synthesized eleven N(4)-(3-bromophenyl)-7-(substitutedbenzyl) pyrrolo[2,3-d]pyrimidines 9a-19a. These compounds were obtained from the key intermediate N(4)-(3-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine 29. Various arylmethyl groups were regiospecifically attached at the N7 of 29 via sodium hydride induced alkylation with substituted arylmethyl halides. Compounds 11a and 19a were potent dual inhibitors of PDGFRβ and VEGFR-2. In a COLO-205, in vivo tumor mouse model 11a demonstrated inhibition of tumor growth, metastasis, and tumor angiogenesis that was better than or comparable to the standard compound TSU-68 (SU6668, 8). 相似文献
12.
Dhawan Sangeeta Pal Anirban Ancha Radhika Bawankule Dnyaneshwar Umrao Yadav Narayan Prasad Darokar Mahendra Pandurang Khanuja Suman Preet Singh 《World journal of microbiology & biotechnology》2009,25(1):161-163
Candida albicans is yeast that is most often associated with serious fungal infections and can cause fungal diseases in immuno-compromised
patients especially patients suffering from AIDS, cancer and cases of organ transplant. Amongst women, candidal vaginitis
is predominantly caused by strains of Candida albicans and also remains to be a common problem in immuno-competent or healthy women. A study was undertaken to assess the efficacy
of a compound CIM 1166 obtained from plant source which was found to possess promising antimicrobial property under in vitro
conditions especially against C. albicans. Taking the lead further, a small animal model utilizing aged Swiss albino females that had parturated at least three times
were taken up for model development. Infection (7 × 106 cfu/ml) was instilled into the vagina in a volume of 20 μl for 3 days. Vaginal washings were aseptically collected on day
4th to confirm the establishment of infection following which the treatment was started which continued for the next 5 days
through vaginal route. Vaginal washings were collected on 6th day and the colony forming units were enumerated on chloramphenicol
incorporated SDA plates. The results indicated that there was a significant decrease in the colony forming units in vaginal
washings (8.0 × 102 cfu/ml) of the treated animals as compared to blank control group (6.0 × 104 cfu/ml). The positive control group administered with clotrimazole also showed a recovery from infection with a fungal load
of 8.78 × 102 cfu/ml. The study proves the efficacy of CIM 1166 in curing vaginal candidiasis in mice, which can be taken up for formulation
development and further studies. 相似文献
13.
Pingali H Jain M Shah S Makadia P Zaware P Goel A Patel M Giri S Patel H Patel P 《Bioorganic & medicinal chemistry》2008,16(15):7117-7127
A few novel 1,3-dioxane carboxylic acid derivatives were designed and synthesized to aid in the characterization of PPAR alpha/gamma dual agonists. Structural requirements for PPARalpha/gamma dual agonism of 1,3-dioxane carboxylic acid derivatives included the structural similarity with potent glitazones in fibric acid chemotype. The compounds with this pharmacophore and substituted oxazole as a lipophilic heterocyclic tail were synthesized and evaluated for their in vitro PPAR agonistic potential and in vivo hypoglycemic and hypolipidemic efficacy in animal models. Lead compound 2-methyl-c-5-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-ylmethoxy)-benzyl]-1,3-dioxane-r-2-carboxylic acid 13b exhibited potent hypoglycemic, hypolipidemic and insulin sensitizing effects in db/db mice and Zucker fa/fa rats. 相似文献
14.
Pingali H Jain M Shah S Patil P Makadia P Zaware P Sairam KV Jamili J Goel A Patel M Patel P 《Bioorganic & medicinal chemistry letters》2008,18(24):6471-6475
Oxazole containing glycine and oximinobutyric acid derivatives were synthesized as PPARalpha agonists by incorporating polymethylene spacer as a replacement of commonly used phenylene group that connects the acidic head with lipophilic tail. Compound 13a was found to be a selective and potent PPARalpha agonist. Further 1,3-dioxane-2-carboxylic acid derivative 20 was synthesized by replacing the tetramethylene spacer of NS-220, a selective PPARalpha agonist with phenylene group and found to exhibit PPARalpha/gamma dual agonism. These results suggest that compounds possessing polymethylene spacer between pharmacophore and lipophilic tail exhibit predominantly PPARalpha agonism whereas those with an aromatic phenylene spacer shows PPARalpha/gamma dual agonism. 相似文献
15.
Harikishore Pingali Mukul Jain Shailesh Shah Pandurang Zaware Pankaj Makadia Suresh Pola Baban Thube Darshit Patel Pravin Patil Priyanka Priyadarshini Dinesh Suthar Maanan Shah Suresh Giri Pankaj Patel 《Bioorganic & medicinal chemistry letters》2010,20(3):1156-1161
Bis-oximinoalkanoic acid derivatives were designed and synthesized to aid in the characterization of selective PPARα agonists by replacing the oxazole ring with flexible oximino group in the lipophilic tail part of a previously reported compound 3. Selected compounds 9d and 9m showed excellent potency and high selectivity towards PPARα in vitro. These compounds found effective in reducing serum triglycerides (TG) in vivo. 相似文献
16.
Ghule VD Srinivas D Sarangapani R Jadhav PM Tewari SP 《Journal of molecular modeling》2012,18(7):3013-3020
The density functional theory (DFT) was employed to calculate the energetic properties of several aminopolynitroazoles. The calculations were performed to study the effect of amino and nitro substituents on the heats of formation, densities, detonation performances, thermal stabilities, and sensitivity characteristics of azoles. DFT-B3LYP, DFT-B3PW91, and MP2 methods utilizing the basis sets 6-31 G* and 6-311 G (2df, 3p) were adopted to predict HOFs via designed isodesmic reactions. All of the designed aminopolynitroazoles had heats of formation of >220 kJ mol(-1). The crystal densities of the aminopolynitroazoles were predicted with the cvff force field. All of the energetic azoles had densities of >1.83 g/cm(3). The detonation velocities and pressures were evaluated using the Kamlet-Jacobs equations, utilizing the predicted densities and heats of formation. It was found that aminopolynitroazoles have a detonation velocity of about 9.1 km/s and detonation pressure of 36 GPa. The bond dissociation energies for the C-NO(2) and N-NO(2) bonds were analyzed to investigate the stabilities of the designed molecules. The charge on the nitro group was used to assess impact sensitivity in the present study. The results obtained imply that the designed molecules are stable and are expected to be candidates for high-energy materials (HEMs). 相似文献
17.
Ravi Kumar Vyas Devambatla Wei Li Nilesh Zaware Shruti Choudhary Ernest Hamel Susan L. Mooberry Aleem Gangjee 《Bioorganic & medicinal chemistry letters》2017,27(15):3423-3430
To identify the structural features of 9H-pyrimido[4,5-b]indoles as microtubule depolymerizers, pyrimido[4,5-b]indoles 2–8 with varied substituents at the 2-, 4- and 5-positions were designed and synthesized. Nucleophilic displacement of 2,5-substituted-4-chloro-pyrimido[4,5-b]indoles with appropriate arylamines was the final step employed in the synthesis of target compounds 2–8. Compounds 2 and 6 had two-digit nanomolar potency (IC50) against MDA-MB-435, SK-OV-3 and HeLa cancer cells in vitro. Compounds 2 and 6 also depolymerized microtubules comparable to the lead compound 1. Compounds 2, 3, 6 and 8 were effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, mechanisms that are associated with clinical drug resistance to microtubule targeting drugs. Proton NMR and molecular modeling studies were employed to identify the structural basis for the microtubule depolymerizing activity of pyrimido[4,5-b]indoles. 相似文献
18.
Ramya Lakshmi Rajendran Manasi Pandurang Jogalekar Prakash Gangadaran Byeong-Cheol Ahn 《World journal of stem cells》2020,12(12):1492-1510
Mounting evidence has emphasized the potential of cell therapies in treating various diseases by restoring damaged tissues or replacing defective cells in the body. Cell therapies have become a strong therapeutic modality by applying noninvasive in vivo molecular imaging for examining complex cellular processes, understanding pathophysiological mechanisms of diseases, and evaluating the kinetics/dynamics of cell therapies. In particular, mesenchymal stem cells (MSCs) have shown promise in recent years as drug carriers for cancer treatment. They can also be labeled with different probes and tracked in vivo to assess the in vivo effect of administered cells, and to optimize therapy. The exact role of MSCs in oncologic diseases is not clear as MSCs have been shown to be involved in tumor progression and inhibition, and the exact interactions between MSCs and specific cancer microenvironments are not clear. In this review, a multitude of labeling approaches, imaging modalities, and the merits/demerits of each strategy are outlined. In addition, specific examples of the use of MSCs and in vivo imaging in cancer therapy are provided. Finally, present limitations and future outlooks in terms of the translation of different imaging approaches in clinics are discussed. 相似文献
19.
The data deluge in post-genomic era demands development of novel data mining tools. Existing molecular phylogeny analyses (MPAs) developed for individual gene/protein sequences are alignment-based. However, the size of genomic data and uncertainties associated with alignments, necessitate development of alignment-free methods for MPA. Derivation of distances between sequences is an important step in both, alignment-dependant and alignment-free methods. Various alignment-free distance measures based on oligo-nucleotide frequencies, information content, compression techniques, etc. have been proposed. However, these distance measures do not account for relative order of components viz. nucleotides or amino acids. A new distance measure, based on the concept of 'return time distribution' (RTD) of k-mers is proposed, which accounts for the sequence composition and their relative orders. Statistical parameters of RTDs are used to derive a distance function. The resultant distance matrix is used for clustering and phylogeny using Neighbor-joining. Its performance for MPA and subtyping was evaluated using simulated data generated by block-bootstrap, receiver operating characteristics and leave-one-out cross validation methods. The proposed method was successfully applied for MPA of family Flaviviridae and subtyping of Dengue viruses. It is observed that method retains resolution for classification and subtyping of viruses at varying levels of sequence similarity and taxonomic hierarchy. 相似文献
20.
Pingali H Jain M Shah S Basu S Makadia P Goswami A Zaware P Patil P Godha A Giri S Goel A Patel M Patel H Patel P 《Bioorganic & medicinal chemistry letters》2008,18(20):5586-5590
A series of novel 1,3-dioxane-2-carboxylic acid derivatives containing alkyl chain tether and substituted phenyl group as a lipophilic tail have been prepared as agonists of PPARalpha and gamma. c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid 13c exhibited potent hypoglycemic and lipid lowering activity with high oral bioavailability in animal models. 相似文献