(1S,2E,4S,7E,11E)-2,7,11-Cembratriene-4,6-diol semisynthetic analogs as novel c-Met inhibitors for the control of c-Met-dependent breast malignancies

Abstract

(1S,2E,4S,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (1) and its 4-epi-analog (2) are the cembranoid precursors to several key flavor ingredients in most Nicotiana (tobacco) species. Nearly 40–60% of 1 and 2 are purposely degraded during the commercial tobacco fermentation. However, 1 and 2 display promising bioactivities, including anticancer. Breast cancer is the most diagnosed cancer in women and ranked second female disease killer. The receptor tyrosine kinase c-Met correlates with aggressiveness of certain breast cancer phenotypes and thus considered a valid therapeutic target. This study reports the discovery and optimization of the tobacco-based cembranoid 1 as a novel c-Met inhibitory scaffold using combined structure- and ligand-based approaches. 1 displayed antiproliferative, anti-migratory and anti-invasive effects against the c-Met overexpressing MDA-MB-231 breast cancer cells at moderate μM concentrations. The Z′-LYTE kinase platform and Western blot analysis identified c-Met as a potential macromolecular target. Rationally designed carbamate analogs were proposed to probe additional targeted c-Met interactions and improve the cellular potency. The 6-phenyl carbamate 3 showed enhanced c-Met inhibitory activity. Structure-activity relationships of different substituents on the 3’s phenyl moiety were studied. The most active analog 20 showed potent in vitro anticancer activities against the MDA-MB-231 breast cancer cells at low μM concentrations, with minimal toxicity on the non-tumorigenic MCF-10A mammary epithelial cells. Cembranoid 20 potently inhibited the c-Met catalytic activity in Z′-LYTE kinase assay and various cellular c-Met-driven signaling pathways. Furthermore, 20 displayed a robust antitumor activity in a breast cancer xenograft athymic mouse model and thus promoted to the lead rank. Cembranoids are novel c-Met inhibitors appropriate for future use to control c-Met dependent malignancies.

Graviola (Annona muricata) Exerts Anti-Proliferative, Anti-Clonogenic and Pro-Apoptotic Effects in Human Non-Melanoma Skin Cancer UW-BCC1 and A431 Cells In Vitro: Involvement of Hedgehog Signaling

“…The PENDANT 13 C NMR spectroscopy method is a J-modulation polarization transfer carbon sequence in which methylene and quaternary carbons are aligned up while the methyl and methine carbons are aligned down [ 36 , 37 , 38 ]. When applied to the graviola DCM extract ( Figure 7 A), four different signal clusters are apparent: an upfield aliphatic methyl and methylene carbons (δ 0–40), a cluster containing oxygenated methylene and methine carbons (δ 60–80), a group of methylenedioxy, olefinic and/or aromatic carbons (δ 105–152), and finally a group of lactone/ester carbonyl and ketone carbons (δ 165–212).…”

Graviola (<em>Annona muricata</em>) Exerts Anti-Proliferative, Anti-Clonogenic and Pro-Apoptotic Effects in Human Non-Melanoma Skin Cancer UW-BCC1 and A431 Cells <em>In Vitro:</em> Involvement of Hedgehog Signaling

“…1 H and 13 C/PENDANT FT NMR spectra were recorded at 400 and 100 MHz, respectively, on a JEOL Eclipse ECS-400 NMR spectrometer (JEOL Inc., Peabody, MA) equipped with a 5 mm FG/TH autotune probe in CD3Cl, except for the MeOH extract spectrum, which was acquired in CD3OD, using the residual solvent peak as internal reference [69][70][71]. A relaxation delay of 3 seconds was used in the PENDANT experiment instead of the default 2 seconds.…”

“…negative ion mode using Analyst version 1.4.1 software (MDS Sciex, Toronto, Canada) [69][70][71]. For MS, about mg of dry DCM extract was dissolved in mL of HPLC-grade methanol, filtered and used for analysis.…”

Quantitative analysis of cembranoids in tobacco leaf by using heart‐cutting two‐dimensional liquid chromatography

“…The (1S,2E,4S,6R,7E,11E)‐2,7,11‐cembratriene‐4,6‐diol (α‐CBT‐diol) and (1S,2E,4R,6R,7E,11E)‐2,7,11‐cembratriene‐4,6‐diol (β‐CBT‐diol) (Figure ) were the main cembranoids in tobacco leaf. What's more, these two diols of α‐CBT‐diol and β‐CBT‐diol were related with the taste and aroma of cigarettes . A wide range of medical values for α‐CBT‐diol and β‐CBT‐diol were reported, for instance, activities against breast and prostate cancers, protective effect against neurodegeneration, antifungal activity and so on .…”

“…What's more, these two diols of α‐CBT‐diol and β‐CBT‐diol were related with the taste and aroma of cigarettes . A wide range of medical values for α‐CBT‐diol and β‐CBT‐diol were reported, for instance, activities against breast and prostate cancers, protective effect against neurodegeneration, antifungal activity and so on . Therefore, it is necessary to develop a rapid, accurate and valid method for the quantitative determination of the cembranoids.…”