Development Of Related Compounds Research Articles

Synergy of novel coumarin derivatives and tamoxifen in blocking growth and inducing apoptosis of breast cancer cells

Possible synergistic effect of tamoxifen (2 μM) and hydrazinyldiene-chroman-2,4-diones (10-100 μM) was examined with an aim to create more effective treatment for ER+ breast cancer. Anti-breast cancer effect has been evaluated on the proliferation of MCF-7 breast adenocarcinoma cells using MTT and alamarBlue assays. Cell viability was evaluated after 48h-treatment and the ICs50 of the coumarin derivatives were determined. The apoptotic effect was evaluated by detection of PARP cleavage and reduced activity of the survival kinase Akt. The results demonstrated dose-dependent activity, with a percent of growth inhibition after combination treatment being significantly higher (53% to 79%, 10 μM and 100 μM, respectively) than the one in the cell lines treated with tamoxifen (29% to 37%) and the synthesized coumarin derivatives alone (11% to 68%, 10 μM and 100 μM, respectively). The ICs50 of the synthesized compounds significantly decreased in synergy with tamoxifen (33% to 51%). Coumarin derivative having thiazole moiety with additional methyl groups attached to the carbons at positions 5 and 4 in the thiazole ring showed to be the most potent, with IC50 20 µM when administered alone and 10 µM in synergy with tamoxifen. The levels of phospho-Thr308 Akt were down-regulated by the combination treatment, pointing to tyrosine kinase phosphorylation inhibition. In conclusion, the novel coumarin derivatives enhance the activity of tamoxifen and this combination may be suitable for prevention of ER+ breast cancer or development of related compounds. Further studies are needed to elucidate precisely the type of receptor involved in the activity and the mechanism of action.

TMC-95A–D and analogues: Chemistry and biology

Abstract The proteasome regulates diverse intracellular processes, including cell-cycle progression, cell adhesion and migration, apoptosis and antigen presentation: selective inhibitors of the proteasome, therefore, have great therapeutic potential for the treatment of cancer. TMC-95A–D are unique natural products and represent a new class of noncovalent, reversible, and selective proteasome inhibitors with exceptionally strong bioactivity profiles and interesting structural properties. Significant recent advances in the syntheses of these natural products have led to intense interest in the development of related compounds as potential anticancer agents: the chemistry and biology of these natural products and analogues will be described in this review article.

Pyrrolidinyl‐Spirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents

The 3,3'-pyrrolidinyl-spirooxindole unit is a privileged heterocyclic motif that forms the core of a large family of alkaloid natural products with strong bioactivity profiles and interesting structural properties. Significant recent advances in the synthesis of this fused heterocyclic system have led to intense interest in the development of related compounds as potential medicinal agents or biological probes.

The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1β and TNF-α

Excessive synovial fibroblast (SF) proliferation is detrimental in rheumatoid arthritis. We therefore sought to determine the effects of A77 1726, the active metabolite of leflunomide, on SF proliferation. Human SFs were used. Cell proliferation was investigated using MTS assay, by (3)H-thymidine incorporation and cell counts. Whereas A77 1726 alone had no effects, it significantly increased the mitogenic effects of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Cyclooxygenase inhibition might be at least partly involved, since indomethacin displayed similar effects, and since prostaglandin E2 inhibited SF proliferation. In contrast, the effect of A77 1726 did not appear to be mediated through depletion of the pyrimidine pool or inhibition of tyrosine kinases. A77 1726 displays proliferative effects in presence of IL-1beta and TNF-alpha. Further elucidation of involved mechanisms may prove useful for the utilization of leflunomide, the development of related compounds or elaboration of new therapeutic strategies.

Use of Suramin in Treatment of Prostatic Carcinoma Refractory to Conventional Hormonal Manipulation

Suramin and related compounds, in view of their growth factor and enzyme binding properties, represent in many respects a novel approach to the treatment of cancer. Although in this preliminary analysis of suramin use in the treatment of metastatic prostate cancer, the objective response rate does not appear impressive, much work still needs to be done to optimize suramin's administration to patients and to elucidate its various postulated mechanisms of action. The development of related compounds with more specific enzyme and growth factor antagonist properties is under way.