As a hybrid of two aryl motifs, that is p‐anisyl and mesityl, the 4‐methoxy‐2,6‐dimethylphenyl or “manisyl” substituent offers possibilities for both further structural elaboration as well as enhancing the solubility of the heterocyclic ligands mentioned in the title. A highlight of this work lies in the ability of the manisyl group to endow specific members of this family such as 1 with high fluorescence quantum efficiency.

Despite the great advances in the synthesis of diverse nonplanar graphenoids, investigations into the relationship between structural features and intermolecular interactions still present significant challenges. Herein, the novel nonplanar graphenoid structure, corannurylene pentapetalae (CRP), obtained via bottom-up syntheses of hybridization between perylene diimide (PDI) planar fragments and a corannulene curved core, is presented. Single crystal studies reveal a D 5-symmetric as well as a C 2-symmetric graphenoid corannurylene pentapetalae. The D 5-symmetric structure has a unique honeycomb lattice with two chiral honeycomb layers alternately stacked, whereas the C 2-symmetric CRP forms dimer units via π–π stacking. Transistor devices demonstrate that, without any π–π stacking, the honeycomb lattice of the D 5-symmetric CRP has the potential to also facilitate electron transport.

Integration of the human immunodeficiency virus type 1 (HIV-1) cDNA is a required step for viral replication. Integrase, the virus-encoded enzyme important for integration, has not yet been exploited as a target for clinically useful inhibitors. Here we report on the identification of new polyhydroxylated aromatic inhibitors of integrase including ellagic acid, purpurogallin, 4,8,12-trioxatricornan, and hypericin, the last of which is known to inhibit viral replication. These compounds and others were characterized in assays with subviral preintegration complexes (PICs) isolated from HIV-1-infected cells. Hypericin was found to inhibit PIC assays, while the other compounds tested were inactive. Counterscreening of these and other integrase inhibitors against additional DNA-modifying enzymes revealed that none of the polyhydroxylated aromatic compounds are active against enzymes that do not require metals (methylases, a pox virus topoisomerase). However, all were cross-reactive with metal-requiring enzymes (restriction enzymes, a reverse transcriptase), implicating metal atoms in the inhibitory mechanism. In mechanistic studies, we localized binding of some inhibitors to the catalytic domain of integrase by assaying competition of binding by labeled nucleotides. These findings help elucidate the mechanism of action of the polyhydroxylated aromatic inhibitors and provide practical guidance for further inhibitor development.

Of three enzymes encoded by HIV-reverse transcriptase, protease, and integrase-only the first two have been exploited clinically as inhibitor targets. Efforts to develop inhibitors of purified integrase protein have yielded many compounds, but none with clinical utility. A different source of integration activity for studies in vitro is provided by replication intermediates isolated from HIV-infected cells. These preintegration complexes (PICs) can direct integration of the endogenously synthesized viral cDNA into an added target DNA in vitro. Despite their authentic activities, assays of PICs have not been widely used due to technical obstacles, particularly the requirement for handling large amounts of infectious HIV. Here, we describe greatly improved methods for producing PICs using HIV-based vectors that are capable of establishing an integrated provirus but not a spreading infection. We also report the development of a PIC integration assay using DNA-coated microtiter plates, which speeds assays of PIC integration in vitro. We used this method to screen a library of chemicals related to known integrase inhibitors and found a new compound, quinalizarin sulfate, that displayed enhanced activity against PICs.

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