Letters in Drug Design & Discovery - Volume 8, Issue 10, 2011

The combined activity of MGBG (metylglyoxal-bis(guanylhydrazone)) with either cisplatin or carboplatin was investigated, towards the human breast cancer cell line MCF-7. While a dose- and time-dependent cytotoxic activity was already observed for MGBG alone, a synergistic and non-reversible effect was verified upon co-administration with these Pt-based drugs. Furthermore, toxicity against non-neoplastic cells was shown to be quite low for these drug cocktails, as opposed to either Pt-agents alone. These results may hopefully allow to use lower dosages of both MGBG and the Ptdrugs, minimising the drug's deleterious side effects while keeping antitumour efficacy, in an anticancer strategy that couples interference with polyamine homeostasis with DNA damage.

Platinum-based chemotherapeutic agents such as carboplatin, cisplatin, and oxaliplatin are used to treat a broad range of malignant diseases. Their efficacies in most cancers are limited by the development of resistance. There are multiple factors that contribute to platinum resistance but alterations of DNA repair processes have been known for some time to be important in mediating resistance. The two anticancer drug candidates Titanocene Y and Vanadocene Y (bis- [(p-methoxybenzyl)cyclopentadienyl] titanium(IV) and vanadium(IV) dichloride) were investigated against the wild-type as well as the platinum-resistant human colon cancer cells HCT-8. Both metallocene drugs were able to break the cisplatin-, carboplatin- and oxaliplatin-resistance in the newly generated corresponding sub-clones of the HCT-8 cells by showing resistance factors ranging from 1.0 - 1.2 for Titanocene Y and 1.1 - 1.6 for Vanadocene Y. In addition, drug uptake and DNA assays were performed using HCT-8 cells again and ICP-MS as the analytical method. High DNA-adduct levels were obtained at IC50 concentrations of Titanocene as well as Vanadocene, which indicates that DNA is a target for these metallocene drugs leading to apoptosis in platinum-resistant HCT-8 cells.

Two C5-substituted licofelone derivatives were developed and investigated for cytotoxicity against mammary (MCF-7 and MDA-MB 231) as well as colon carcinoma (HT-29) cancer cells. Both compounds were at least 2-fold more active than 5-fluorouracil (5-FU) and licofelone against mammary carcinoma cells. At HT-29 cells, they were less active, but nevertheless distinctly as active as 5-FU and still 2-fold more active than licofelone. However, variation of the C5- carboxylic group results in an occasionally remarkable decrease of anti-inflammatory potency in in vitro and in vivo.

A quantitative structure-activity relationship (QSAR) study has been made on a novel series of substituted 3-[3-(aminopropyl)-4,5,6,7-tetrahydro-1H-indol-2-ylmethylene]-1,3-dihydro-indole-2-ones as potent inhibitors of the non-receptor Src tyrosine kinase. The activity is found to be significantly correlated with calculated hydrophobicity and molar refractivity of the molecule. The correlation obtained suggests that the activity of the compounds is controlled by the hydrophobic and steric properties of the molecules. The internal and external validation of the correlation is judged by calculating r2cv (= 0.66) for the training set and r2pred (= 0.52) for test set. Using the correlation, some new compounds have been predicted possessing higher potencies than the compounds in the existing series.

The growth and metastasis of solid tumors are dependent on angiogenesis. The vascular endothelial growth factor (VEGF) is of particular interest since it is essential for angiogenesis. The development of novel inhibitors of VEGF receptor type 2 (VEGFR-2) is important. Quantitative structure-activity relationship (QSAR) studies were performed to understand the structural factors affecting inhibitory potency of 4-aryl-5-cyano-2-aminopyrimidines. Docking studies were performed to explore the binding mode between all of the inhibitors and the VEGFR-2 and produce the bioactive conformation of each compound in the whole dataset. The docked conformer-based alignment strategy gave the 3DQSAR models. Both CoMFA (q2= 0.575, r2 = 0.903, and r2predictive = 0.763) and CoMSIA (q2 = 0.617, r2 = 0.869, and r2predictive = 0.783) gave reasonable results. The contour maps obtained from 3D-QSAR studies were evaluated for activity trends for the molecules analyzed. CoMSIA models exhibited good external predictivity as compared with that of CoMFA models. The data generated from the present study helped us to predict the activity of new inhibitors and further design some novel and potent VEGFR-2 enzyme inhibitors.

Estrogens are responsible for the growth of hormone-dependant breast cancer. Regulation of estrogen biosynthesis is considered as a potential therapeutic strategy for the control of breast cancer. The enzyme aromatase catalyzes conversion of androgens into estrogens in the last step of estrogen biosynthesis. Inhibition of aromatase is adopted as an efficient approach for the prevention and treatment of breast cancer. Many steroidal and nonsteroidal aromatase inhibitors have been developed and are used clinically for breast cancer therapy. In this report, it has been tried to incorporate some structural features (six membered lactam ring) of nonsteroidal aromatase inhibitors like aminoglutethimide and rogletimide into the A-/D-ring of the steroid nucleus with certain additional features responsible for binding to the enzyme aromatase. Some ring-A [17β-hydroxy-4-(4-substitutedphenyl)-4-aza-5-androsten-3-one] and ring-D modified steroidal compounds [4-substituted-17a-aza-D-homo-4-androstene-3,17-dione, 4-substituted-17-aza-Dhomo- 4-androstene-3,16,17a-trione, 4-substituted-17a-methyl-17a-aza-D-homo-4-androsten-3-one] were synthesized and screened for binding to the aromatase enzyme. None of the synthesized compounds showed promising aromatase inhibiting activity leading to the conclusion that structurally the original androstane ring skeleton should not be tampered with, for obtaining good aromatase inhibiting activity.

SSH-BM-I is a new synthetic compound that is synthesized from Bromomelatonin by using a newly developed synthetic method. Recently, our group demonstrated that SST-VED-I-1, which has a similar chemical structure to SSHBM- I, inhibits starvation-induced apoptosis in osteoblasts. However, the effects of SSH-BM-I on apoptosis in osteoblasts have not yet been examined. Therefore, this study examined the effects of this compound on apoptosis in osteoblasts. In the present study, MC3T3-E1 mouse osteoblasts were used and apoptosis was induced by ultraviolet radiation (UV). We investigated the effect of SSH-BM-I on apoptosis by analyzing Caspase3/7 activity, translocation of Phosphatidylserine (PS), and mRNA expression levels of Bcl-2 and Bax. We found that SSH-BM-I suppressed UV-induced cell death in a dose-dependent manner, which was accompanied with the inhibition of Caspase activation and translocation of PS. Furthermore, SSH-BM-I up-regulated Bcl-2 expression and down-regulated Bax expression. These results suggest that SSH-BM-I has an inhibitory effect on apoptosis in osteoblasts through a Bcl-2 family-dependent signaling pathway.

A series of new cinnamide dimers was synthesized (5a-6a) and evaluated for their antimicrobial and antifungal activity. All the compounds investigated have shown significant antimicrobial activity against gram-positive and gram-negative bacterial strains, as well as few fungal strains. The compounds having withdrawing group exhibited significant biological activity than their precursors. Moreover all the compounds containing electron withdrawing substituent showed good antimicrobial activity in comparison with the standards.

A series of novel 4” -O-2-arylbenzimidazolyl derivatives of clarithromycin were synthesized and evaluated. These 4” -O-2-arylbenzimidazolyl derivatives demonstrated excellent activity against erythromycin-susceptible strains and showed remarkably improved activity against erythromycin-resistant strains compared with the references. In particular, compound 7c, which possesses the terminal 2-(2-methoxyphenyl)benzimidazolyl group on the C-4” bishydrazide side chain, not only presented the most potent activity against erythromycin-susceptible Streptococcus pneumoniae ATCC49619 and Staphylococcus aureus ATCC25923, exhibiting 4-fold and 4-fold higher efficacy than the parent clarithromycin, but also displayed the highest activity against erythromycin-resistant Streptococcus pneumoniae expressing the mef gene and the erm gene, which was 133-fold and 32-fold better than clarithromycin or azithromycin, respectively.

New anacardic acid derivatives (5a -5s) were prepared from commercially available anacardic acid and tested for Gram positive and Gram negative bacteria. Most compounds were found to be active compared to ampicillin drug.

Resistance to commercially available antimicrobials is increasing at alarming rate therefore there is an urgent need of new antimicrobial compounds and materials with novel modes of action to tackle the problem of resistance in pathogenic gram positive and gram negative bacteria. The current study involves the design and synthesis of new molecular structures which should not resemble the basic molecular structures of the existing classes of antimicrobial agents in order to avoid the risks of cross resistance development. A total of 14 metal-barbiturate complexes (newly synthesized compounds) were evaluated for their antimicrobial properties against multiple drug resistance clinical isolates of S. aureus and E. coli. Broth dilution method was used to determine minimum inhibitory and bactericidal activity of the newly synthesized compounds. The results showed that the metal-barbiturate complexes with cobalt ions were more effective against E. coli and S. aureus as compared to other compounds. Moreover the activity of these compounds was higher against S. aureus as compared to E. coli which indicates species specific variable antimicrobial effects of these compounds.

A series of novel 2-methyl-3-(2-(piperazin-1-yl)ethyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one sulfonamide and carboxamide derivatives were synthesized in good yield. The synthesized compounds were characterized by 1H-NMR, FTIR and elemental analysis. All the synthesised compounds were screened for their in vitro antimicrobial activity by agar well diffusion and micro dilution method against standard strains of Gram-positive (Bacillus subtilis MTCC 121, Staphylococcus epidermidis 435), and Gram-negative (Xanthomonas campestris 7903 and Pseudomonas aeruginosa MTCC 7908) bacteria. Compound 7a and compound 8d with dichloro substitution among sulphonamide and carboxamide series respectively showed potent inhibitory activity.

Estrogen, the key regulator of the cellular process involved in the development and maintenance of reproductive functions, mediates its action through estrogen receptor binding, and initiating a series of cellular pathway producing estrogen-induced responses. At higher dose, it can effectively act as contraceptive but associates with risk factors. Considering the long-term benefit-to-risk ratio of estrogen analogs as oral contraceptives, the present in-silico study has been focussed to deduce the active pharmacophore features required to differentiate the anti-fertility potency from estrogenic activity of steroidal motif. Hydrophobicity is an essential property for promoting both the functionalities, but molecular conformation and presence of hydrogen bond acceptors have been deduced to be the distinguishing features of anti-fertility activity of estrogen analogs as revealed from the molecular field and similarity analyses, and receptordependent docking studies.

1,2,4-Triazoles, pyrazoles and semicarbazides possessing heterocyclic ring 1-14 were synthesized as compounds with interesting pharmacological profiles. All were investigated in vitro for their antioxidant activity. Some compounds showed significant effect in the above assay. The most promising was a group of pyrazolone. The effect was dependent mainly on the substituent on the amide group. It was found that compounds 8 and 10 showed the highest antioxidant capacity comparable with the widely used reference, antioxidant 6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxylic acid (Trolox).

In order to understand the molecular mechanism of Tongguan capsule (TGC), a Traditional Chinese Medicine (TCM) for coronary heart disease (CHD), computational approaches of pharmacodynamic modeling were introduced to predict the interaction between drugs and targets about cardiovascular system. Firstly, we employed a molecular docking protocol to study the interaction of natural compounds from TGC and 13 receptors related with CHD, and screened out the potential effective components. Then the distribution of the effective components on ligand-target space was traced out, and two drug-target networks were developed to decipher the multiple components and multiple targets mechanism of TGC. Most importantly, the forecasting results of computational approaches were agreeable with some pharmacological and clinical experiments. The results showed that computational pharmacology can be an efficacious approach for the modern research of TCM in the future.