Search

This is the peer reviewed version of the following article: Deichert, J.A., Mizufune, H., Patel, J.J., Hurst, T.E., Maheta, A., Kitching, M.O., Ross, A.C. and Snieckus, V. (2020), Expedient Pd‐Catalyzed α‐Arylation towards Dibenzoxepinones: Pivotal Manske's Ketone for the Formal Synthesis of Cularine Alkaloids. Eur. J. Org. Chem.. doi:10.1002/ejoc.202000424, which has been published in final form at https://doi.org/10.1002/ejoc.202000424. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

Mitochondrial fission is important in physiological processes, including coordination of mitochondrial and nuclear division during mitosis, and pathologic processes, such as the production of reactive oxygen species (ROS) during cardiac ischemia-reperfusion injury (IR). Mitochondrial fission is mainly mediated by dynamin-related protein 1 (Drp1), a large GTPase. The GTPase activity of Drp1 is essential for its fissogenic activity. Therefore, we aimed to identify Drp1 inhibitors and evaluate their anti-neoplastic and cardioprotective properties in five cancer cell lines (A549, SK-MES-1, SK-LU-1, SW 900, and MCF7) and an experimental cardiac IR injury model. Virtual screening of a chemical library revealed 17 compounds with high predicted affinity to the GTPase domain of Drp1. In silico screening identified an ellipticine compound, Drpitor1, as a putative, potent Drp1 inhibitor. We also synthesized a congener of Drpitor1 to remove the methoxymethyl group and reduce hydrolytic lability (Drpitor1a). Drpitor1 and Drpitor1a inhibited the GTPase activity of Drp1 without inhibiting the GTPase of dynamin 1. Drpitor1 and Drpitor1a have greater potency than the current standard Drp1 GTPase inhibitor, mdivi-1, (IC50 for mitochondrial fragmentation are 0.09, 0.06, and 10 μM, respectively). Both Drpitors reduced proliferation and induced apoptosis in cancer cells. Drpitor1a suppressed lung cancer tumor growth in a mouse xenograft model. Drpitor1a also inhibited mitochondrial ROS production, prevented mitochondrial fission, and improved right ventricular diastolic dysfunction during IR injury. In conclusion, Drpitors are useful tools for understanding mitochondrial dynamics and have therapeutic potential in treating cancer and cardiac IR injury.

Application of radical cross-dehydrogenative coupling (CDC) procedures to prepare a range of novel spirocyclic oxindoles and to a formal total synthesis of the vasopressin V2 receptor antagonist Satavaptan is reported. The key step involves a copper-mediated oxidative cyclisation of a simple linear anilide precursor to give the spirocyclic oxindole core. This synthetic approach was also used to prepare novel Satavaptan scaffolds and analogues.

A new cyclisation procedure to prepare 4-carboxy-quinolin-2-ones via a one-pot Cu(II)-mediated radical cross-dehydrogenative coupling/sulfinic acid elimination of linear anilides is described. Extensions to more complex substrates are also reported as are applications in target synthesis allowing access to natural products isolated from Oryza sativa and HOFQ.

The naturally occurring 1,4-benzoquinones 2-methoxy-6-propyl-1,4-benzoquinone (1), 2-methoxy-6-pentyl-1,4-benzoquinone (primin 2), 2-methoxy-6-pentadecyl-1,4-benzoquinone (3), 2-methoxy-6-heptadecyl-1,4-benzoquinone (dihydroirisquinone, pallasone B; 4) were synthesized by a simple protocol involving microwave accelerated Claisen rearrangement of allyl ethers 10, followed by hydrogenation of the side chain alkene, and oxidation to the quinone. The Claisen-based methodology was extended to the first synthesis of the marine benzoquinones verapliquinones A and B (5 and 6), and panicein A (7). Isoarnebifuranone (9) was also synthesized by a similar strategy.

The synthesis of acridanes and related compounds through a Cu‐catalysed radical cross‐dehydrogenative coupling of simple 2‐[2‐(arylamino)aryl]malonates is reported. This method can be further streamlined to a one‐pot protocol involving the in situ fomation of the 2‐[2‐(arylamino)aryl]malonate by α‐arylation of diethyl malonate with 2‐bromodiarylamines under Pd catalysis, followed by Cu‐catalysed cyclisation.