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1.
J Org Chem ; 89(7): 5126-5133, 2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38466932

ABSTRACT

In this study, we introduce a convenient Heck vinylation protocol that eliminates the requirement for ethylene gas as a coupling partner. In contrast to traditional methodologies, quaternary ammonium salts can serve as solid olefin precursors under ambient atmosphere conditions. The practicality of this method, distinguished by its convenience and safety in a one-pot reaction, renders it appealing for applications in research and discovery context.

2.
J Med Chem ; 66(9): 6122-6148, 2023 05 11.
Article in English | MEDLINE | ID: mdl-37114951

ABSTRACT

Avoidance of apoptosis is critical for the development and sustained growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins which is overexpressed in many cancers. Upregulation of Mcl-1 in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Therefore, pharmacological inhibition of Mcl-1 is regarded as an attractive approach to treating relapsed or refractory malignancies. Herein, we disclose the design, synthesis, optimization, and early preclinical evaluation of a potent and selective small-molecule inhibitor of Mcl-1. Our exploratory design tactics focused on structural modifications which improve the potency and physicochemical properties of the inhibitor while minimizing the risk of functional cardiotoxicity. Despite being in the "non-Lipinski" beyond-Rule-of-Five property space, the developed compound benefits from exquisite oral bioavailability in vivo and induces potent pharmacodynamic inhibition of Mcl-1 in a mouse xenograft model.


Subject(s)
Antineoplastic Agents , Hematologic Neoplasms , Humans , Mice , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemistry , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Cell Line, Tumor , Apoptosis , Hematologic Neoplasms/drug therapy , Proto-Oncogene Proteins c-bcl-2/metabolism
3.
J Org Chem ; 87(4): 2136-2141, 2022 02 18.
Article in English | MEDLINE | ID: mdl-34570981

ABSTRACT

MCL-1 is an attractive target for cancer therapy. We recently discovered highly potent and selective MCL-1 inhibitors containing a fluoroalkene fragment for which an efficient route to the main chiral gem-fluoro-BPin fragment was needed. The key step of this synthesis is a highly stereoselective defluoroborylation of a gem-difluorovinyl intermediate. The latter is reached via a copper-catalyzed diastereoselective opening of dimethyloxirane. These two features allowed a 30-fold improvement in yield, a shorter synthesis, and a decrease in the cost of this crucial building block.


Subject(s)
Antineoplastic Agents , Antineoplastic Agents/pharmacology , Copper , Myeloid Cell Leukemia Sequence 1 Protein , Stereoisomerism
4.
J Med Chem ; 64(19): 14175-14191, 2021 10 14.
Article in English | MEDLINE | ID: mdl-34553934

ABSTRACT

The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pKa and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 (12), which gave robust dose-dependent BACE1-mediated amyloid ß lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that 12 has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, 12 was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Drug Discovery , Pyrrolidines/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Structure-Activity Relationship
5.
Chemistry ; 23(62): 15594-15600, 2017 Nov 07.
Article in English | MEDLINE | ID: mdl-29024056

ABSTRACT

Stereoselective functionalization of aliphatic C-H bonds presents a great challenge. Following this target, we disclose herein an original strategy towards direct arylation of aliphatic chains at ß-methylene position based on a use of amide-sulfoxide bicoordinating directing group. Although moderate to high chiral induction (up to 9:1 d.r.) is achieved, diastereomerically pure compounds may be afforded by simple separation of diastereomeric products by silica gel chromatography. Accordingly, this reaction allows preparation of a large scope of high-value scaffolds in synthetically useful yields while recyclable character of our chiral auxiliary brings an additional benefit. A potential of this methodology to build up original molecules by sequential diarylation and expedient (two step) synthesis of a biologically active compound are further disclosed. Finally a first example of stereoselective direct acetoxylation of aliphatic chains is reported.

6.
Chemistry ; 22(48): 17397-17406, 2016 Nov 21.
Article in English | MEDLINE | ID: mdl-27792256

ABSTRACT

An original and recyclable chiral bidentate aniline-sulfoxide-based directing group has been developed. This auxiliary allows challenging stereoselective Pd-catalyzed direct functionalization of small cycloalkanes through C-aryl and C-alkyl bond formation. Although moderate diastereoselectivities are observed, both optically pure enantiomers of the highly functionalized products can be obtained separately by simple silica gel chromatography and cleavage of the chiral auxiliary. This strategy was further applied to the preparation of enantiomerically pure 1,2,3-trisubstituted cyclopropane carboxylic acid derivatives, with three stereogenic centers and bearing both alkyl and aromatic substituents. These molecular scaffolds are not yet reported in the literature. The synthetic utility of this approach is validated by the chiral auxiliary being readily cleaved and recovered posteriori to the C-H activation step, without deterioration of its optical purity. Finally, an unprecedented palladacycle intermediate generated through C-H activation of the cyclopropane moiety has been isolated and fully characterized. Initial DFT calculations shed additional light on the reactivity of this original intermediate.

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