Letters in Drug Design & Discovery - Volume 10, Issue 5, 2013

The indole-substituted titanocene dichloride derivative Titanocene T, which is completely water-soluble and shows micromolar activity against the human renal cancer cells Caki-1, was tested in vivo an against xenografted human renal cell tumors in mice. Titanocene T was then given at 25 and 50 mg/kg, seven times every four days during three weeks to two groups (n=6) of Caki-1 tumor-bearing female NMRI:nu/nu mice, while the control group was treated with solvent only. At both doses Titanocene T induced a moderate to good tumor growth reduction with respect to the solventtreated control group, with an optimal T/C value of 51% and 32% and showed neither mortality nor toxicity. Immunohistochemical analysis revealed that the expression of the proliferation marker Ki-67 was reduced in the high-dosage group. Furthermore, anti-angiogenic activity was identified by CD31 staining; the number of micro vessels in a defined tumor area decreased by 27% and 29% due to Titanocene T treatment.

A series of 3-chloro-4-(indol-3-yl)-2,5-pyrroledione derivatives were synthesized and evaluated for their cytotoxic activities in vitro against five human cancer cell lines (K562, A549, ECA-109, KB and SMMC-7721). Most compounds displayed potent cytotoxicity with IC50 values in low micromolar range. The results showed that the existence of the chlorine atom at 3-position on the pyrroledione ring was crucial for the activity. Compound 6a, the most potent one (IC50: 0.67∼3.93 μM), would be a promising template for further development of novel antitumor agents

Scolopendra subspinipes mutilans, also known as Chinese red-headed centipede, is a venomous centipede from East Asia and Australasia. In traditional Chinese medicine, this centipede has been widely used for the treatment of various ailments, but few researches on the venom from this centipede have been conducted so far. In the present study, we reported that the venom could potently suppress the growth of the myelogenous leukemia cell lines K562, U937 and HL- 60, in a dose-dependent manner with IC50 values of 20 μg/mL, 30 μg/mL, 200 μg/mL, respectively. K562 cells treated with the venom showed typical morphological indicators of apoptosis including condensation of nuclei. Annexin V-FITC and propidium iodide double staining further demonstrated that the venom had potent apoptogenic activity. Venom treatment induced caspase 2, 3, 6, 8 and 9 activation in K562 cells, which might involve in the venom-induced apoptosis. The venom could also cause cell cycle arrest. Increased cell accumulation at S phase was observed in K562 cells treated with the venom. Taken together, the Chinese red-headed centipede venom could inhibit the growth of myelogenous leukemia cell lines through apoptosis induction and cell cycle arrest. It might be a useful source for the identification of substances with anti-leukemia activity.

In this paper, a recently reported series of NPS antagonists is further expanded and biologically evaluated. The ligand efficiency and ADMET score concepts were then applied to the newly disclosed 5-phenyl-2-[2-(1-piperidinylcarbonyl) phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-ones, to limit the SAR exploration. Important pharmacophoric features were identified suggesting potential way forward for the identification of further developable templates.

To discover the lead compounds with better antitumor activity, the synthesis and cytotoxic activities of fatty acid esters of 20(S)-protopanaxatriol (PPT) were investigated in this study. 22 fatty acid esters of PPT, including two known oleoy esters and other 20 new fatty acid esters, were synthesized using acyl chloride or fatty acid and N, N'- dicyclohexylcarbodiimide (DCC). The structures were elucidated by the combined analysis of NMR and ESI-MS. The antitumor activities were tested in vitro in three cell lines, HepG2, Hela and SGC-7901, using the MTT method for the first time. The structural relationships between fatty acid derivatives of PPT and their cytotoxic properties were also discussed preliminarily in this paper.

The glyoxalase enzymes represent a cellular defence system against the accumulation of cytotoxic α- oxoaldehydes leading to apoptosis. The potential of glyoxalase inhibitors to act as novel anti-cancer agents for drugresistant tumours that over-express glyoxalase is currently under investigation. In the present study, a series of 6- sulfamoylsaccharin and 1,2-benzoxathiine 2,2-dioxide (sulfocoumarin - coumarin bioisostere) derivates, as well as, transcinnamic acid (the mimic of coumarin hydrolysis product) have been tested for the inhibition of glyoxalase 1 and 2. For the first time, it has been demonstrated, that 6-sulfamoylsaccharin possesses glyoxalase 1 inhibitory activity (IC50=90±15 μM). Two compounds, 5b and 9c, slightly inhibited the activity of glyoxalase 2. In addition, it has been demonstrated that trans-cinnamic acid inhibits glyoxalase 1 activity (IC50=84±4 μM). These data indicate that the modification of 6- sulfamoylsaccharin structure and coumarin hydrolysis products can be used to develop potential glyoxalase 1 inhibitors.

Hyperglycemia has been shown to be the major risk factor responsible for the systemic complications that are the cause of morbidity and mortality in patients with diabetes. The elevated glucose concentration in blood, activates several pathways such as polyol pathway, PKC pathway, hexosamine pathway and plays an important role not only in cataract but also in the pathogenesis of diabetic complications such as neuropathy, nephropathy and retinopathy. The activation of polyol pathway through aldose reductase enzyme leads to accumulate sorbitol in tissues during diabetic stage. Accumulation of sorbitol causes diabetic complications such as cataract, kidney disease. Inhibition of aldose reductase enzyme activity would be an effective treatment of diabetic complications. In the present study, 21 thiazolyl-2,4- thiazolidinediones (TZDs) (compounds 1-21) were tested for their probable inhibitory ability on kidney aldose reductase enzyme. The enzyme activity was determined spectrophotometrically by monitoring NADPH oxidation which accompanies the reduction of D -L-glyceraldehyde which is used as substrate. The inhibition study was performed merely by using 10-4 M concentration of each drug and IC50 values of compounds 1-6, 16-21 were studied. 10-4, 10-5 and 10-6M concentrations were performed for calculating IC50 values. Compound 1 (5-((2, 4-dichlorothiazol-5-yl) methylene) thiazolidine-2, 4-dione) is showed the greatest inhibition capacity with the rate 91.11%. TZD-derivatives which have the compound numbers 2, 5, 16 and 20 are followed the compound 1 with the inhibition capacities of 77.50%, 81.31%, 77.36% and 78.97%, respectively. All the remaining TZD-derivatives are showed inhibitory activity between the rates 4.00 - 76.58 %.

As STAT3 has been validated as an anticancer target, its inhibitors have been shown to possess therapeutic promise for the treatment of human cancers. To identify novel and selective STAT3 inhibitors, a virtual screening based on the STAT3 SH2 domain was performed and a small molecule, 2-phenylquinoline-4-carboxylic acid (5a), with an inhibition constant Ki value of 17.53 μM to STAT3 was discovered. On this basis, the derivatives of 5a including esters, amides and dimers were synthesized. The bioactivity and inhibitory selectivity of the derivatives were assayed using human breast cancer cell lines, MDA-MB-468 and MCF-7. Among the derivatives, 5c and 9b showed the most potent inhibitory activity with a good selectivity, and also inhibited STAT3 protein level of MDA-MB-468 cells. The results demonstrated a successful application of virtual screening for lead discovery. Compound 9b might be an effective STAT3 inhibitor lead for the further development of antitumor agents.

Quantitative Structure Activity Relationship (QSAR) studies using CoMFA and CPSA parameters were carried out on tetranortriterpenoids exhibiting diverse antifeedant activity to obtain models with high predictive ability. Satisfactory results with good statistical parameters were obtained from both methods. CoMFA gave a reasonably better predictive model with a cross-validated r2 value of 0.654 and a conventional r2 value of 0.953 for all compounds; however the analysis with CPSA parameters yielded better results only when the compounds were analyzed as individual classes based on their geometry. Single equation involving the chosen descriptors, based on their r2 values, for each class of compounds was calculated and a correlation was drawn between the experimental and calculated values, corroborated by good statistical parameters. The enhancement in the antifeedant activity of the photo products and the reduction in the activity of the microwave modified compounds are well brought out from the above studies. The present analysis reveals that better prediction models using CPSA parameters can be obtained by class wise analysis of the compounds.

In vitro activities of methanol and water (crude) extracts of leaves, barks and seeds from Cassia fistula were tested against Gram-positive and Gram-negative bacteria by using disc-diffusion method at 6.25-100 μg/μl. Of which water extracts of leaf showed powerful antibacterial action against Proteus vulgaris and Staphylococcus aureus than others. Six (6) purified compounds from the most active leaves displayed higher antibacterial activity than the compound (2) and (4) against P. vulgaris and S. aureus. In vitro toxicological properties were evaluated by MTT assay to test the reduction of viability of human lung (MRC-5), skin (HEPK) fibroblasts and human macrophage (U-937) cells with the C. fistula water-leaf extracts and compounds (6) at 62.5 - 2000 μg/ml doses. The water-leaf extracts -showed less cytotoxic activity on MRC-5 cells than the U-937 and HEPK cells. However, the compound (6) was not toxic to all the human cells up to 1000 μg/ml doses. In conclusion, the significant antibacterial activity may be due to the compound flavonoids and the toxicity results proved the traditional usage of this plant for bacterial therapy.

In an attempt to develop effective antimicrobial therapeutics, a new series of pyrazoles incorporating 1,3,5- oxadiazole and 1,2,4-triazole moieties and their S-glycosides has been synthesized. All the newly synthesized compounds were confirmed by IR, 1H, 13C NMR and mass spectral studies. The newly synthesized compounds were tested for their antimicrobial activity against two fungal species and two bacterial species. The obtained data indicated that some of the tested compounds exhibited both antibacterial and antifungal activities, particularly compounds 14, 16, 17 and 18 showed a comparable effect to a well known antibacterial and antifungal agent.

In this study, N-(benzothiazol-2-yl)-2-(piperidin-1-yl)acetamide derivatives (1-24) were obtained by the reaction of 2-chloro-N-(benzothiazole-2-yl)acetamides with piperidine derivatives. The structures of the compounds were elucidated by 1H-NMR and mass spectral data and elemental analysis. The compounds were screened for their antimicrobial activities against pathogenic bacteria and Candida species. The compounds were also investigated for their cytotoxic properties using MTT assay. The microbiological results revealed that the compounds were more effective against fungi than bacteria. Among Candida species, C. utilis was the most susceptible fungus to compounds 7 and 11. It is apparent that 2,6-dimethylpiperidine group and chloro and methyl substituents on benzothiazole ring have an important impact on anticandidal activity. MTT assay indicated that the effective doses of these derivatives were lower than their cytotoxic doses.

Single step construction of heterocyclic α-aminonitriles has been carried out using Indium Powder as catalyst in water medium via Strecker reaction methodology. The multicomponent reaction products were examined for their inhibitory potential against two Gram-positive bacteria (S. aureus and B. cereus), three Gram-negative bacteria (E. coli, P. aeruginosa and K. pneumoniae) and two fungal species (A. niger and C. albicans). The biological screening identified that the some compounds were found to possess promising antimicrobial (6.25-50 μg/mL of MIC) potential. A structure– activity relationship (SAR) study was explored to facilitate further development of this new class of compounds. The structural assignments of the new products were done on the basis of IR, 1H NMR, 13C NMR spectroscopy and elemental analysis.

A series of 14-diarylidene-1-phenethylpiperidine-4-one derivatives were synthesized using Claisen-Schmidt condensation reactions. The synthesized compounds were screened for their antimycobacterial activity against Mycobacterium tuberculosis (MTB) H37Rv using High Throughput Screen (HTS) using an assay adapted from the microdilution alamarBlue (AB) broth assay reported by Collins and Franzblau and additionally an alternative method for end-point detection was assessed using the Promega reagent BacTiter-Glo™ Microbial Cell Viability (BTG). Most of the compounds showed low-to-moderate activity with MIC of less than 30μM. Compound (3d) (3E,5E)-3,5-bis (4-triflouromethylbenzyledene)- 1-phenethylpiperidin-4-one was found to be the most active with MIC of 27.00 μM.