We investigated effects of hydrogen passivation of edges of armchair graphene nanoribbons (AGNRs) on their electronic properties using first-principles method. The calculated band gaps of the AGNRs vary continually over a range of 1.6 eV as a function of a percentage of sp3-like bonds at the edges. This provides a simple way for band gap engineering of graphene as the relative stability of sp2 and sp3-like bonds at the edges of the AGNRs depends on the chemical potential of hydrogen gas, and the composition of the sp2 and sp3-like bonds at the edges of the AGNRs can be easily controlled experimentally via temperature and pressure of H2 gas.
Total synthesis of the complex polycyclic indole alkaloid (±)-communesin F has been accomplished in 23 reaction steps in about 3% overall yield. The key steps relied on a highly efficient methodology for assembling the pentacyclic substructure 2 with the C7 quaternary carbon, the stereoselective preparation of the second C8 quaternary carbon by a two-step one-pot O-allylation and consecutive 3,3-rearrangement (2 to 3), and the stereoselective acid-catalyzed cyclization of 4 to form the azepine ring (5). These highly stereoselective reactions guaranteed the stereochemical results, allowing the construction of the C, E, F, and G ring systems.
The first total synthesis of the akuammiline alkaloid (+/-)-vincorine (6) has been accomplished in about 1% overall yield in 31 steps. A concise assembly of the core 1,2-disubstituted 1,2,3,4-tetrahydro-4a,9a-iminoethanocarbazole (1), a distinctive feature of akuammiline and strychnos alkaloids, was developed via a three-step one-pot cascade reaction consisting of copper-catalyzed intramolecular cyclopropanation, ring-opening, and ring closure. The construction of the last seven-membered E-ring in a rigid two-ring moiety (31, 45 to 47) through Heck coupling, Michael addition, pi-allyl/Heck or pi-allyl/Stille coupling failed, leading us to seek an alternative method. After successful addition of an acetate side chain on C15 of the cyclohexenyl ring (D-ring) in Boc-protected 35b by a Johnson-Claisen rearrangement and multistep modification of the functionality in the rearrangement product 33a, the E-ring formation was then realized for providing pentacyclic lactam 32 through intramolecular condensation of the acid group on the D-ring and the amine group on the C-ring with Mukaiyama's reagent. An E-ethylidenyl group on the E-ring was stereoselectively added to afford lactam 56a through a two-step reaction of 32 consisting of aldol addition with acetaldehyde and cis-elimination of the resulting hydroxyl group. Final elaboration of 56a, including opening of the seven-membered E-ring, selective reduction of the alpha,beta-unsaturated ester, and reclosure of the seven-membered E-ring completed the total synthesis of 6.
Background: While PARP inhibitors and CDK4/6 inhibitors, the two classes of FDA-approved agents, have shown promising clinical benefits, there is an urgent need to develop new therapeutic strategies to improve clinical response. Meanwhile, extending the utility of these inhibitors beyond their respective molecularly defined cancer types is challenging and will likely require biomarkers predictive of treatment response especially when used in a combination drug development setting. Methods: The effects of PARP inhibitor Olaparib and CDK4/6 inhibitor Palbociclib on ovarian cancer cells lines including those of high-grade serous histology were examined in vitro and in vivo. We investigated the molecular mechanism underlying the synergistic effects of drug combination. Findings: We show for the first time that combining PARP and CDK4/6 inhibition has synergistic effects against MYC overexpressing ovarian cancer cells both in vitro and in vivo. Mechanistically, we find that Palbociclib induces homologous recombination (HR) deficiency through downregulation of MYC-regulated HR pathway genes, causing synthetic lethality with Olaparib. We further demonstrate that MYC expression determines sensitivity to combinatorial treatment with Olaparib and Palbociclib. Interpretation: Our data provide a rationale for clinical evaluation of therapeutic synergy of these two classes of inhibitors in ovarian cancer patients whose tumors show high MYC expression and who do not respond to PARP inhibitors or CDK4/6 inhibitors monotherapies.
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