Discovery of (4-Pyrazolyl)-2-aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2.

CDK2 is a critical regulator of the cell cycle. For a variety of human cancers, the dysregulation of CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts to develop CDK2 inhibitors with clinical applications proved unsuccessful due to challenges in achieving selectivity over off-target CDK isoforms with associated toxicity. In this report, we describe the discovery of (4-pyrazolyl)-2-aminopyrimidines as a potent class of CDK2 inhibitors that display selectivity over CDKs 1, 4, 6, 7, and 9. SAR studies led to the identification of compound 17, a kinase selective and highly potent CDK2 inhibitor (IC50 = 0.29 nM). The evaluation of 17 in CCNE1-amplified mouse models shows the pharmacodynamic inhibition of CDK2, measured by reduced Rb phosphorylation, and antitumor activity.

Asymmetric synthesis of (-)-dehydro-exo-brevicomin with a photoisomerisation-intramolecular acetalisation sequence.

We herein report a novel, short asymmetric synthesis of (-)-dehydro-exo-brevicomin (DHB, 1), a sex pheromone isolated from house mice, in 44% overall yield, the highest yield reported so far, over eight steps from trans-3-hexen-1-ol (7). We successfully prepared the target molecule (-)-1 from spontaneous intramolecular acetalisation after the photoisomerisation of trans-enone 6, which generated the corresponding cis-enone 5in situ, the possible biosynthetic precursor of DHB.

A unified strategy to reverse-prenylated indole alkaloids: total syntheses of preparaherquamide, premalbrancheamide, and (+)-VM-55599.

A full account of our studies toward reverse-prenylated indole alkaloids that contain a bicyclo[2.2.2]core is described. A divergent route is reported which has resulted in the synthesis of preparaherquamide, (+)-VM-55599, and premalbrancheamide. An intramolecular Dieckmann cyclization between an enolate and isocyanate was used to forge the bicyclo[2.2.2]diazaoctane core that is characteristic of these molecules. The pentacyclic indole scaffold was constructed through a one-pot Hofmann rearrangement followed by Fischer indole synthesis. The utilization of our previously reported indole peripheral functionalization strategy also led to natural products including malbrancheamides B, C, stephacidin A, notoamides F, I and R, aspergamide B, and waikialoid A. Ultimately, the divergent route that we devised provided access to a wide range of prenylated indole alkaloids that are differently substituted on the cyclic amine core.

Elucidation of Racemization Process of Azaspirene Skeleton in Neutral Aqueous Media.

Azaspirene and related congeners, which possess various biological activities, have a unique spirocyclic core structure. However, there are few studies on the chemical properties of (-)-azaspirene, despite the fact that it may provide important insights into unveiling the biosynthetic pathway. Here, we report a nine-step chemical synthesis of an azaspirene analogue with a new finding that the natural (-)-azaspirene skeleton easily racemizes in neutral aqueous media.

Total Synthesis and Biological Evaluation of 19-Hydroxysarmentogenin-3 -O-α-l-rhamnoside, Trewianin, and Their Aglycons.

Cardenolides comprise an important family of natural steroids with a wide spectrum of biological activities. Although 19-hydroxysarmentogenin-3- O-α-l-rhamnoside (1a) and trewianin (1b) were structurally determined to have cardenolide structures, their biological activities have not been evaluated. The 6/6/6/5-membered ABCD-ring systems of both 1a and 1b are decorated by a ß-oriented C17-butenolide, three C11,14,19-hydroxy groups, and a C3-O-l-rhamnoside moiety. On the other hand, 1a and 1b are epimeric at the C5-position. The structures of 1a and 1b were assembled from four simple fragments by applying a convergent and unified strategy. The AB-ring 10a/b and the D-ring 8/9 were tentatively tethered at the acetal moiety, and a subsequent stereoselective 6- exo radical reaction linked the two fragments. Next, an aldol reaction enabled simultaneous introduction of three new stereocenters of the C-rings of 5aa and 54. Attachment of the C17-butenolide led to aglycons 2a and 2b. l-Rhamnose was then installed into 2a and 2b to yield the targets 1a and 1b, respectively. Finally, the growth inhibitory activity of 1a, 1b, 2a, and 2b was assessed against MCF-7 human breast carcinoma cells. The significantly higher activities of 1a and 1b in comparison to 2a and 2b demonstrated the biological importance of the monosaccharide substructure.

Bioinspired chemical synthesis of monomeric and dimeric stephacidin A congeners.

Stephacidin A and its congeners are a collection of secondary metabolites that possess intriguing structural motifs. They stem from unusual biosynthetic sequences that lead to the incorporation of a prenyl or reverse-prenyl group into a bicyclo[2.2.2]diazaoctane framework, a chromene unit or the vestige thereof. To complement biosynthetic studies, which normally play a significant role in unveiling the biosynthetic pathways of natural products, here we demonstrate that chemical synthesis can provide important insights into biosynthesis. We identify a short total synthesis of congeners in the reverse-prenylated indole alkaloid family related to stephacidin A by taking advantage of a direct indole C6 halogenation of the related ketopremalbrancheamide. This novel strategic approach has now made possible the syntheses of several natural products, including malbrancheamides B and C, notoamides F, I and R, aspergamide B, and waikialoid A, which is a heterodimer of avrainvillamide and aspergamide B. Our approach to the preparation of these prenylated and reverse-prenylated indole alkaloids is bioinspired, and may also inform the as-yet undetermined biosynthesis of several congeners.

A convergent total synthesis of ouabagenin.

A convergent total synthesis of ouabagenin, an aglycon of cardenolide glycoside ouabain, was achieved by assembly of the AB-ring, D-ring and butenolide moieties. The multiply oxygenated cis-decalin structure of the AB-ring was constructed from (R)-perillaldehyde through the Diels-Alder reaction and sequential oxidations. The intermolecular acetal formation of the AB-ring and D-ring fragments, and combination of the intramolecular radical and aldol reactions, assembled the requisite steroidal skeleton in a stereoselective fashion. Finally, stereoselective installation of the C17-butenolide via the Stille coupling and hydrogenation led to ouabagenin.

High-speed carbon nanotube actuators based on an oxidation/reduction reaction.

Actuators with a high-speed response under a high-frequency (more than 100 Hz) applied square-wave voltage of ±2 V have been developed with an electrode composed of millimeter-long single-walled carbon nanotubes synthesized by the "supergrowth method" (SG-SWNTs) and ionic liquids (ILs). Detailed studies concerning induced electric current and transferred charge in the electrode as well as cyclic voltammetric studies of the electrode revealed that the high-speed response originates from the electric current generated by an oxidation/reduction (redox) reaction in addition to electric double-layer charging. The contribution of the redox reactions of SG-SWNTs to the actuation is sensitive to the presence of supporting polymers, the thickness of the electrolyte, and the amplitude of the applied voltage.