Discovery of ZN-c3, a Highly Potent and Selective Wee1 Inhibitor Undergoing Evaluation in Clinical Trials for the Treatment of Cancer.

Wee1 inhibition has received great attention in the past decade as a promising therapy for cancer treatment. Therefore, a potent and selective Wee1 inhibitor is highly desirable. Our efforts to make safer and more efficacious Wee1 inhibitors led to the discovery of compound 16, a highly selective Wee1 inhibitor with balanced potency, ADME, and pharmacokinetic properties. The chiral ethyl moiety of compound 16 provided an unexpected improvement of Wee1 potency. Compound 16, known as ZN-c3, showed excellent in vivo efficacy and is currently being evaluated in phase 2 clinical trials.

Efficacy and mechanism of action of Deguelin in suppressing metastasis of 4T1 cells.

Cancer related deaths in breast cancer patients are due to metastasis of the disease. Murine 4T1 cells (Murine mammary cancer cell line developed from 6-thioguanine resistant tumor) provide an excellent research tool for metastasis related studies because these cells are highly aggressive and readily metastasize to the lungs. In this study we determined the effect of Deguelin on in vivo/vitro growth and metastasis of 4T1 cells. Deguelin inhibited the in vitro growth of 4T1 cells in a time and dose dependent manner accompanied with reduced nuclear PCNA immunostaining. In cells treated with Deguelin, reduced expression of nuclear c-Met, and its downstream targets such p-ERK and p-AKT was observed. Deguelin reduced the cell migration in 4T1 cells as determined by scratch wound assay. Combined treatment with Deguelin + ERK or PI3K/AKT inhibitor had no additional effect on cell migration. These results indicated that the action of Deguelin on cell migration may be mediated by AKT and ERK mediated signaling pathways. In vivo, Deguelin treatment significantly inhibited growth of 4T1 cells. Deguelin also reduced the occurrence of metastatic lung lesions by 33 % when cells were injected intravenously into Balb/c female mice. There was no difference in the body weight, nor was there a difference in liver and spleen weights between vehicle treated-control and Deguelin-treated animals, which indicated that Deguelin was nontoxic at the dose used in the present study. These results provide rationale for developing Deguelin as a chemotherapeutic agent for triple negative breast cancer patients.

Total syntheses of lyconadins A-C.

The total synthesis of the Lycopodium alkaloid lyconadin A was accomplished and it was applied to the total syntheses of the related congeners, lyconadins B and C. Lyconadin A has attracted attention as a challenging target for total synthesis due to the unprecedented pentacyclic skeleton. Our synthesis of lyconadin A features a facile construction of the highly fused tetracyclic skeleton through a combination of an aza-Prins reaction and an electrocyclic ring opening, followed by formation of a C-N bond. Transformation of the bromoalkene moiety of the tetracycle to a key enone intermediate was extensively investigated, and three methods via sulfide, oxime, or azide intermediates were established. A pyridone ring was constructed from the key enone intermediate to complete the synthesis of lyconadin A. A dihydropyridone ring could also be formed from the same enone intermediate, leading to a synthesis of lyconadin B. Establishment of the conditions for an electrocyclic ring opening without formation of the C-N bond resulted in completion of the total synthesis of lyconadin C.

Concise total synthesis of (+)-lyconadin A.

The total synthesis of lyconadin A from (R)-5-methylcyclohex-2-enone was accomplished. Our synthesis features the facile construction of a highly fused tetracyclic compound through a combination of an aza-Prins reaction and an electrocyclic ring opening. Transformation of the bromoalkene moiety in the tetracycle could be achieved by either a vinylogous Pummerer rearrangement or the formation and subsequent isomerization of the nitrosoalkene to furnish an α,ß-unsaturated ketone, from which the pyridone ring was constructed.

Axially chiral biaryl diols catalyze highly enantioselective hetero-Diels-Alder reactions through hydrogen bonding.

Axially chiral 1,1'-biaryl-2,2'-dimethanol (3, BAMOL) family of diols are highly effective catalysts for enantioselective hetero-Diels-Alder reactions between aminosiloxydiene 1 and a wide variety of unactivated aldehydes. The reactions proceed in useful yields and excellent enantioselectivities. The diols function in the same capacity as Lewis acids, by activating the aldehyde carbonyl group through hydrogen bonding.