Naturally occurring cinnamic acid derivatives are ubiquitously distributed in the plant kingdom, and it has been proposed that their consumption contributes to the maintenance of human health. However, the molecular mechanisms underlying their health keeping effects remain unknown. In the present investigation, we evaluated the capacity of several cinnamic acid derivatives (trans-cinnamic, p-coumaric, caffeic and ferulic acids, as well as caffeic acid-methyl and -propyl esters) to protect cells from oxidative stress-induced DNA damage. It was observed that effective protection was based on the ability of each compound to (i) reach the intracellular space and (ii) chelate intracellular "labile" iron. These results support the notion that numerous lipophilic iron chelating compounds, present abundantly in plant-derived diet components, may protect cells in conditions of oxidative stress and in this way be important contributors toward maintenance of human health.
A concise and stereoselective synthesis of the highly oxygenated D‐ring of the kinamycin family of antitumor antibiotics was achieved from commercially available 3‐methyl‐2‐cyclohexen‐1‐one. The key steps included a regioselective isomerization of a cis‐epoxy alcohol, a regioselective reductive ring opening of a benzylidene ketal, and a stereoselective α‐hydroxy‐directed ketone reduction. The Ullmann coupling between a bromonaphthaldehyde AB‐ring fragment and an α‐iodocyclohexenone, which is a versatile D‐ring precursor, effected the construction of the functionalized ABD‐ring system that may provide access to kinamycin F and its structural analogues.
This thesis entails a strategy for the synthesis of the kinamycin family of antitumor antibiotics and its structural analogues, where a concise and stereoselective synthesis of the highly oxygenated D-ring as well as the construction of the ABD-ring system of kinamycins was achieved. Access to the highly oxygenated D-ring was provided from commercially available 3-methylcyclohexen-2-one, with key steps including a regioselective isomerization of a cis-epoxyalcohol, a regioselective reductive opening of a benzylidene ketal and a stereoselective α-hydroxy directed ketone reduction.Model studies indicated that the assembly of the ABD-ring system of kinamycins was feasible via a metal-catalyzed Ullmann coupling reaction strategy. Indeed, coupling of a highly oxygenated cyclohexenone D-ring with a bromonaphthaldehyde AB-ring fragment, gave access to a highly functionalized kinamycin ABD-ring intermediate that may provide access to kinamycin F and its structural analogs.Furthermore, the chemistry that was developed here may be amenable to asymmetric synthesis and provide access to optically active material.
Receptor activator of nuclear factor-κB ligand (RANKL) has been actively pursued as a therapeutic target for osteoporosis, given that RANKL is the master mediator of bone resorption as it promotes osteoclast differentiation, activity and survival. We employed a structure-based virtual screening approach comprising two stages of experimental evaluation and identified 11 commercially available compounds that displayed dose-dependent inhibition of osteoclastogenesis. Their inhibitory effects were quantified through TRAP activity at the low micromolar range (IC50 < 5 μΜ), but more importantly, 3 compounds displayed very low toxicity (LC50 > 100 μΜ). We also assessed the potential of an N-(1-aryl-1H-indol-5-yl)aryl-sulfonamide scaffold that was based on the structure of a hit compound, through synthesis of 30 derivatives. Their evaluation revealed 4 additional hits that inhibited osteoclastogenesis at low micromolar concentrations; however, cellular toxicity concerns preclude their further development. Taken together with the structure–activity relationships provided by the hit compounds, our study revealed potent inhibitors of RANKL-induced osteoclastogenesis of high therapeutic index, which bear diverse scaffolds that can be employed in hit-to-lead optimization for the development of therapeutics against osteolytic diseases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.