Structure-based drug design and potent anti-cancer activity of tricyclic 5:7:5-fused diimidazo[4,5-d:4′,5′-f][1,3]diazepines

Abstract

Judicial structural modifications of 5:7-fused ring-expanded nucleosides (RENs), based on molecular modeling studies with one of its known targets, human RNA helicase (hDDX3), led to the lead, novel, 5:7-5-fused tricyclic heterocycle (1). The latter exhibited promising broad-spectrum in vitro anticancer activity against a number of cancer cell lines screened. This paper describes our systematic, albeit limited, structure-activity relationship (SAR) studies on this lead compound, which produced a number of analogs with broad-spectrum in vitro anticancer activities against lung, breast, prostate, and ovarian cancer cell lines, in particular compounds 15i, 15j, 15m and 15n which showed IC50 values in submicromolar to micromolar range, and are worthy of further explorations. The SAR data also enabled us to propose a tentative SAR model for future SAR efforts for ultimate realization of optimally active and minimally toxic anticancer compounds based on the diimidazo[4,5-d:4′,5′-f][1,3]diazepine structural skeleton of the lead compound 1.

RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3

“…3A), which serves as a DDX3 inhibitor with radiosensitizing properties. RK-33 has anticancer activity in lung cancer, as well as many other cancer types, including breast cancer and sarcoma (16, 17, 19, 32). An MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetra-zolium) assay of RK-33 treatment showed that DU145, LNCaP, and 22Rv1 were sensitive to RK-33 at half-maximal inhibitory concentration (IC 50 3–6 μmol/L), whereas PC3 was much less sensitive to RK-33 (IC 50 >12 μmol/L; Fig.…”

“…The putative functions of DDX3 have been associated with a variety of cellular functions, including cell-cycle progression, cellular proliferation, and apoptosis under various conditions (12–15). On the basis of the crystallographic structure of DDX3, we rationally designed a small-molecule inhibitor, RK-33, which has been demonstrated to bind to DDX3 and inhibit its helicase activity in breast and lung cancer cell lines (6, 16–18). RK-33 inhibits proliferation of multiple lung cancer cell lines in a dose-dependent manner and acts as a radiosensitizer in lung cancer mice models (19).…”

Structure‐Based Design of Inhibitors of the Aspartic Protease Endothiapepsin by Exploiting Dynamic Combinatorial Chemistry

“…Saturation-transfer difference (STD) NMR spectroscopy, which enables the direct characterization of target-ligand interactions in solution, [3] has been applied to identify DCL members bound to the target. [5] Whereas de novo SBD is rarely used, [6] most reports on SBD deal with the optimization of an initial hit discovered by other means. [5] Whereas de novo SBD is rarely used, [6] most reports on SBD deal with the optimization of an initial hit discovered by other means.…”

Unprecedented Synthesis of 2‐Aminochromones and 2‐Aminoquinolones through an Electrophilic C–Cyanation and 6‐exo‐dig Cyclization Cascade with the Intermediary of β‐Ketonitriles

“…In the field of medicinal chemistry, aza‐heterocycles constitutes the fundamental pharmacophore units of various heterocyclics present in bioactive compounds. Consequently several synthetic methods were evolved to construct these heterocyclic ring systems.…”