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In BRCA2-defective cells, poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors can trigger synthetic lethality, as two independent DNA-repairing mechanisms are simultaneously impaired. Here, we have pharmacologically induced synthetic lethality, which was triggered by combining two different small organic molecules. When administered with a BRCA2-Rad51 disruptor in nonmutant cells, Olaparib showed anticancer activity comparable to that shown when administered alone in BRCA2-defective cells. This strategy could represent an innovative approach to anticancer drug discovery and could be extended to other synthetic lethality pathways.

Aryldiazepin-2-ones are known as "privileged structures", because they bind to multiple receptor types with high affinity. Toward the development of a novel class of aryldiazepin-2-one scaffolds, the synthesis of pyrrolo[3,2-e][1,4]diazepin-2-ones on a support was explored starting from N-(PhF)-4-hydroxyproline and featuring an acid-catalyzed Pictet-Spengler reaction to form the diazepine ring. Three supports [Wang resin, tetraarylphosphonium (TAP) soluble support, and Merrifield resin] were examined in the synthesis of the heterocycle and exhibited different advantages and disadvantages. Wang resin proved effective for exploratory optimization of the synthesis by identification of intermediates after resin cleavage under mild conditions; however, the acidic conditions of the Pictet-Spengler reaction caused premature loss of resin-bound material. Direct monitoring of reactions by TLC, RP-HPLC-MS, and in certain cases NMR spectroscopy was possible with the TAP support, which facilitated purification of intermediates by precipitation; however, incomplete precipitation of material led to overall yields lower than those from solid-phase approaches on resin. Merrifield resin proved stable to the conditions for the synthesis of the pyrrolo[3,2-e][1,4]diazepin-2-one targets and would be amenable to "split-and-mix" chemistry; however, relatively harsh conditions were necessary for final product cleavage. Perspective for the application of different solid-phase approaches in heterocycle library synthesis was thus obtained by demonstration of the respective utility of the three supports for preparation of pyrrolo[3,2-e][1,4]diazepin-2-one.

Direct preparation of beta,beta-disubstituted C- and N-vinylindoles from condensation of aldehydes on indole derivatives is presented. Heating 1-methyl- and 1-benzylindole 3a,b with alkyl and aryl alpha-branched aldehydes and TFA in acetonitrile using microwave irradiation furnished 3-vinylindoles 1a-e in 18-76% yields. Under similar conditions, 3-substituted indoles 4a-c provided N-vinylindoles 2a-h in 16-98% yields.

Incorporation of amino lactams into biologically active peptides has been commonly used to restrict conformational mobility, enhance selectivity, and increase potency. A solid-phase method using a Fmoc-protection strategy has been developed for the systematic synthesis of peptides containing configurationally defined alpha- and beta-amino gamma-lactams. N-Alkylation of N-silyl peptides with five- and six-member cyclic sulfamidates 9 and 8 minimized bis-alkylation and provided N-alkyl peptides, which underwent lactam annulation under microwave heating. Employing this solid-phase protocol on the growth hormone secretagogue GHRP-6, as well as on the allosteric modulator of the IL-1 receptor 101.10, has furnished 16 lactam derivatives and validated the effectiveness of this approach on peptides bearing aliphatic, aromatic, branched, charged, and heteroatomic side chains. The binding affinity IC(50) values of the GHRP-6 lactam analogues on both the GHS-R1a and CD36 receptors are reported as well as inhibition of thymocyte proliferation measurements for the 101.10 lactam analogues. In these cases, lactam analogues were prepared exhibiting similar or improved properties compared with the parent peptide. Considering the potential for amino lactams to induce peptide turn conformations, the effective method described herein for their supported construction on growing peptides, and for the systematical amino lactam scan of peptides, has proven useful for the rapid identification of the secondary structure necessary for peptide biological activity.