Letters in Drug Design & Discovery - Volume 12, Issue 7, 2015

DMU-212, a methoxylated resveratrol analog, has significant anticancer activity, and selectively targets tumor cells. A library of E-diarylstilbenes structurally related to DMU-212 has been synthesized and evaluated for anticancer activity against a large panel of 45 human cancer cell lines. From this study, DMU-212 (3a) exhibited an average growth inhibitory effect (GI50) of 3.5 μM against all the human cancer cell lines in the panel, and was particularly effective against the four cancer cell lines: SNB-75 (CNS), MDA-MB-435 (melanoma), A498 (renal), and MCF7 (breast), with GI50 values of 1.88, 1.04, 0.74 and 1.66 μM, respectively. Also, the 4’-chloro analog of DMU-212, 3d, exhibited 98 and 80 percent growth inhibition against MDA-MB-435 (melanoma) and K-562 (leukemia) cancer cell lines at a concentration of 10 μM. Further investigation of DMU-212 and its analogs may provide novel therapeutic avenues for treatment of a variety of human cancers.

A series of 6-bromo-2,3-dioxoindolin phenylacetamide derivatives was synthesized and evaluated for inhibitory activity against CDC25B and PTP1B. Most of the synthesized compounds showed potential inhibitory activities for CDC25B and PTP1B with compound 12 being the most potent (IC50=3.87 μmol/L and 2.98 μmol/L, respectively). Compound 12 also exhibited higher cytotoxic activity against three cancer cell lines (HeLa, A549 and HCT116). In addition, compound 12 delayed the potent tumor inhibitory activity in a colo205 xenograft model in vivo.

During the last century, flavonoids have been identified as multifunctional compounds with properties and biological activities that depend on their diverse functional groups, which may include hydroxyl, methyl, methoxy, glycosyl, isoprenyl, and various polymeric groups. In particular, methoxy groups located on the basic flavonoid structure are intimately interrelated to bioavailability and translocation in cells. The relationships between structure and activity of 23 flavones, including a methoxylated flavone, were evaluated with regard to their cytotoxic effects in cervical cancer cells. Comparative molecular field analyses (CoMFA) and comparative molecular similarity index analyses (CoMSIA) were performed to improve predictive 3D-QSAR models. Models generated from CoMFA and CoMSIA yielded cross-validated correlation coefficient values (q2) of 0.602 and 0.537, and non-cross-validated values (r2) of 0.964 and 0.965, respectively. Thus, this study provides valuable information on the suitability of modified flavones as chemotherapeutic agents. In addition, CoMFA and CoMSIA contour maps were used to design and structurally modify a flavone compound with functional groups to maximize its anticancer effects.

From various studies it is now clear that in addition to nucleic acids, enediynes also target other biomolecules, the most prominent of which are the proteins. Since a major portion of currently available drug targets are proteins (enzymes and receptors), this aspect of enediyne chemistry has opened a new window for further exploitation. Newer enediyne-based therapeutics targeting proteins may be possible to design. Moreover, the toxicity of the natural enediynes may arise from the non-selective protein cleavages. Substantial progress has been made to understand the nature of interaction between enediynes and proteins. This article is an attempt to discuss the developments in this area.

Monopolar spindle 1 (Mps1), a crucial component of spindle assembly checkpoint, essential to maintain the chromosomal stability, is an attractive cancer drug target. Now the accessibility to multiple crystal structures of Mps1 ligand complexes and inhibitors with known biological activities have accelerated the identification of novel molecular scaffolds by means of computer. In this paper, we developed the structure-based and ligand-based phormacophores, and the two approaches were cascaded together for comparative analysis. The multiple pharmacophore models were evaluated using enrichment analysis. Then the six models were used for virtual screening of chemical databases. The retrieved compounds with novel scaffolds and good fitness were further refined by docking studies and ADME profiling. Finally, 16 hits were identified and the binding modes observed through docking the hits to the ATP binding domain gave valuable insights into the relationship between structural features and inhibitory activity. The present research work provides valuable information for rational design of potent and selective Mps1 agents.

Five Lapatinib derivatives were designed by structurally modifying the side chain as well as the aniline substituent. The ELISA assay showed that the derivatives retained or even improved the inhibitory activity of Lapatinib against HER1/HER2. In vitro cytotoxicity assay revealed that the derivatives significantly inhibited the proliferation of the HER1/HER2-overexpressing cancer cells. Furthermore, molecular modeling study suggested that the derivative could effectively enter the ATP binding pocket of HER1 and interact with the corresponding residues in a manner similar to Lapatinib.

Osteoarthritis is no doubt a difficult disease to manage. Targeted delivery of drugs to bone may not only enhance the treatment efficacy, but also reduces the quantity of drug administered. In this paper, we have synthesized two series of NSAID-Glu oligopeptide conjugates built up by the therapeutic moiety (naproxen and ibuprofen) and the targeting moieties (Glutamic oligopeptides) via amide linkage, as novel potential bone-targeting NSAIDs prodrugs. Preliminary studies indicated that these prodrugs exhibited outstanding hydroxyapatite affinity, furthermore, NSAIDs-glutamic hexa-peptide conjugates were found more potent in hydroxyapatite binding. The adequate chemical stability of the conjugates in different buffers, indicated that the conjugates might become a promising approach of selective delivery of drugs to bone tissues. These results may be conducive to the study of bone targeting drugs delivery.

Various bioisosteres of ethyl pyruvate (EP), where the oxygen atom in the ethoxy group was replaced by the corresponding bioisosteric atom such as carbon, nitrogen, and sulfur atoms, were synthesized and their inhibitory effects were tested for nitric oxide (NO) production and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-induced BV2 cells. The synthesized compounds generally revealed better activity than EP. Especially, the thio-bioisostere 4c (IC50 = 3.6 μM) exhibited a potency about 4.5 times greater than that of EP (IC50 = 16.1 μM) and suppressed NO production dose-dependently without cytotoxicity. Compound 4c also inhibited iNOS expression in LPS-induced BV2 cells at 1 μM and 10 μM concentrations. These results suggested that the ethoxy group in EP is not essential for the suppression of NO production and that 4c has potential as a potent inhibitor of NO production.

In the present study, a series of dibenzoazepine triazole derivatives (24-39) were synthesized and evaluated for their in vitro bioactivities including antiglycation, antibacterial, DPPH radical scavenging, urease inhibition, antileishmanial and immunomodulatory activities. The compounds were found to be moderately active only against leishmania. Within this series, compound 26 was found to be the most active antileishaminals with IC50 value 37.4 ± 0.4 μM. Structure-activity relationships for this novel class are discussed.

Some furan-based chalcone derivatives were synthesized via the Claisen-Schmidt condensation of 5-arylfurfural derivatives with 4'-cyanoacetophenone. The synthesized derivatives were investigated for their antimicrobial activity using a broth microdilution assay. Among these compounds, 1-(4-cyanophenyl)-3-[5-(4-nitrophenyl)-2-furyl]-2-propen-1-one (4) can be considered as the most promising antimicrobial agent against Enterococcus faecalis (ATCC 51922) and Candida albicans. Compound 4 showed antimicrobial activity against E. faecalis with a MIC value of 100 μg/mL, whereas chloramphenicol exhibited its antibacterial activity with a MIC value of 200 μg/mL. Compound 4 (MIC = 100 μg/mL) was also more effective than ketoconazole (MIC = 200 μg/mL) against C. albicans. Microbiological assay pointed out the importance of p-nitro substituent for antimicrobial activity.