Hemisynthesis and cytotoxic evaluation of manoyl oxide analogs from sclareol: effect of two tertiary hydroxyls & Heck coupling on cytotoxicity.

Sclareol, a bioactive diterpene alcohol isolated from Salvia sclarea, was subjected to structural modification and cytotoxic evaluation. Boron-Heck-coupled analogs of manoyl oxide were prepared from sclareol in a two-step reaction scheme. In the first step manoyl oxide was prepared from sclareol using cerium (IV) ammonium nitrate. Further the structural modification of manoyl oxide via Palladium (II) catalysed Boron-Heck coupling reaction produced a new series of compounds. All the synthesised compounds were screened for in vitro cytotoxic evaluation against four cancer cell lines HCT-116, MCF-7, MDA-MB231and MDA-MB468. The results showed that manoyl oxide is less active than sclareol. Sclareol shows an IC50 of 2.0 µM compared to manoyl oxide with an IC50 of 50 µM against the MCF-7 cell line. From the results it was inferred that the presence of two tertiary hydroxyls in sclareol are necessary for its cytotoxic activity and Heck coupled analogs are more active than sclareol and manoyl oxide.

Heterochiral dipeptide d-phenylalanyl- l-phenylalanine (H-D Phe-L Phe-OH) as a potential inducer of metastatic suppressor NM23H1 in p53 wild-type and mutant cells.

In recent years, significant progress has been made to the use-case of small peptides because of their diversified edifice and hence their versatile application scope in cancer therapy. Here we identify the heterochiral dipeptide H-D Phe-L Phe-OH (F1) as a potent inducer of the metastatic suppressor NM23H1. We divulge the effect of F1 on the major EMT/metastasis-associated genes and the implications on the invasion and migration ability of cancer cells. The anti-invasive potential of F1 was directly correlated with NM23H1 expression. Mechanistically, F1 treatment elevated p53 levels as validated by localization and transcriptional studies. In the NM23H1 knockdown condition, F1 failed to induce any p53 expression/nuclear localization, indicating that the upregulation in p53 expression by F1 is NM23H1 dependent. We also demonstrate how the antimetastatic potential of F1 is primarily mediated through NM23H1 irrespective of the p53 status of the cell. However, both NM23H1 and a functional p53 protein in conjunction govern the apoptotic and cytostatic potential of F1. Coimmunoprecipitation studies unraveled the augmentation of the p53 and NM23H1 interaction in p53 wild-type cells. However, in p53 mutated cells, no such enrichment was evidenced. We employed mouse isogenic cell lines (4T-1 and 4T-1 p53) to determine the in vivo efficacy of F1 (spontaneous and experimental models). Decreased tumor volume in the cohort injected with 4T-1 p53 cells demonstrated that while the antimetastatic potential of F1 was reliant on NM23H1, p53 activation was required for ablation of primary tumor burden. Our findings unravel that F1 treatment induces significant abrogation of the migration, invasion and metastatic potential of both p53 wild-type and p53 deficient cancers mediated through NM23H1.