| Natural products provide extraordinarily diverse chemical scaffolds and are often used as starting points for drug discovery. Recently, 3,3’-dihydroxyisorenieratene (DHIR) (Scheme 1), a natural and polymethylated carotenoid of microbial origin, was well-documented to be an excellent antioxidant and photoprotecting agent in model and cell systems. Unfortunately, this molecule has two violations (MWT > 500 and logp >> 5) of Lipinski’s rule of five that determines if a substance is drug-like. Thus, adhering to the concept of "the simple is the best",we attempted to tailor its conjugated link and to improve the flaws, by in turn reducing an isoprene unit, dubbed as an isoprene unit retention truncation strategy. The truncation generated four novel compounds,1-4 (Scheme 1). Among them, this smallest diterpene (1) is structurally similar to resveratrol (RES)and its active analogs 4,4’-dihydroxy-trans-stilbene (4,4’-DHS, Scheme 1). Therefore, as part of our continuing search for RES-inspired antioxidants and cancer chemoprevention agents, we synthesized the above compounds and investigated their cancer chemoprevention activity and mechanism in the dissertation which provides an example of successfully designing a concise lead molecule inspired from a complex natural product, DHIR. The main results are listed as follows:(1) The synthesis of compounds 1-4 was accomplished using the classic McMurry, Wittig and Wittig-Horner olefination approaches according to a divergent strategy allowing the use of common intermediates. Moreover, 1 was further constructed from 4-bromo-2,3,5-trimethylphenol in 65% yield following a one-pot Stille-Heck tandem sequence through the use of tributylvinyltin,bis(tri-tert-butylphosphine)palladium(0) and cesium fluoride as substrate, catalyst and base,respectively. The strategy offers several advantages such as significantly shortening the reaction steps, being protecting-group-free and overcoming the unfavourable steric hindrance.(2) Anti-inflammatory activity of compounds 1-4, RES and its active analog, 4,4’-DHS was evaluated by assaying the inhibition of nitric oxide (NO) production induced by lipopolysaccharide in macrophages (RAW 264.7). Among them, 1 and 4,4-DHS bearing para-dihydroxy groups were the most potent ones. More interestingly, compound 1 turned out to be a promising lead molecule in terms of its selective antiproliferative activity on NCI-H460 cells.Mechanistic study reveals that the activity is not mediated by inducing apoptosis, but by blocking cell cycle in G1 phase via down-regulation of Cdk2, Cdk4, cyclin A and cyclin E. Theoretical calculations and cell uptake experiments indicate that the polymethylation pattern of compounds 1 compared with RES and 4,4’-DHS significantly induces a conformational change shift out of planarity and increases its cell uptake and metabolic stability. These results can explain, at least in part, why it displays better performances and give us useful information for rationally designing RES-inspired antiproliferative agents.(3) A green, protecting-group-free, concise and high efficient synthesis for the symmetrical hydroxystilbene was developed in water by a one-pot Suzuki-Heck tandem sequence. This method not only overcomes the steric hindrance and is free protection of hydroxyl group, but also can effectively construct the 2, 3, or 4-hydroxylation of stilbene and tetrahydroxystilbene.(4) Antioxidant activity of compounds 1-4 and influence of the core polyene system length on the activity were investigated by ferric reducing antioxidant power, cyclic voltammetry,ABTS+-scavenging, human red blood cell hemolysis-protecting and human low-density lipoprotein (LDL) oxidation-inhibiting assays. Our results show that their antioxidant activity and influence of the core polyene system length on the activity depend significantly on the assay models and methods. |
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