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1.
ACS Med Chem Lett ; 14(9): 1179-1187, 2023 Sep 14.
Article in English | MEDLINE | ID: mdl-37736184

ABSTRACT

Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and are frequently altered in cancer cells, thereby leading to uncontrolled proliferation. In this context, CDK2 has emerged as an appealing target for anticancer drug development. Herein, we describe the discovery of a series of selective small molecule inhibitors of CDK2 beginning with historical compounds from our ERK2 program (e.g., compound 6). Structure-based drug design led to the potent and selective tool compound 32, where excellent selectivity against ERK2 and CDK4 was achieved by filling the lipophilic DFG-1 pocket and targeting interactions with CDK2-specific lower hinge binding residues, respectively. Compound 32 demonstrated 112% tumor growth inhibition in mice bearing OVCAR3 tumors with 50 mg/kg bis in die (BID) oral dosing.

2.
J Am Chem Soc ; 139(45): 16377-16388, 2017 11 15.
Article in English | MEDLINE | ID: mdl-29048164

ABSTRACT

We describe the development of an enantioselective synthetic route to (+)-pleuromutilin (1), (+)-12-epi-mutilin, and related derivatives. A key hydrindanone was prepared in three steps and 48% overall yield from cyclohex-2-en-1-one. 1,4-Hydrocyanation provided a nitrile (53%, or 85% based on recovered starting material) that was converted to the eneimide 57 in 80% yield by the 1,2-addition of methyllithium to the nitrile function, cyclization, and in situ acylation with di-tert-butyldicarbonate. The eneimide 57 was employed in a 2-fold neopentylic coupling reaction with an organolithium reagent derived from the alkyl iodides (R)- or (S)-30, which contain the C11-C13 atoms of the target, to provide diastereomeric diketones in 60% or 48% yield (for coupling with (R)- or (S)-30, respectively). The diketone derived from (S)-30 contains the (S)-C12 stereochemistry found in pleuromutilin and was elaborated to an alkynylaldehyde. Nickel-catalyzed reductive cyclization of this alkynylaldehyde, to construct the eight-membered ring of the target, unexpectedly provided a cyclopentene (67%), which arises from participation of the C12-α-olefin in the transformation. The diketone derived from the enantiomeric C12-fragment (R)-30 underwent reductive cyclization to provide the desired product in 60% yield. This was elaborated to 12-epi-mutilin by a four-step sequence (39% overall). Installation of the glycolic acid residue followed by C12 epimerization (Berner et al. Monatsh. Chem. 1986, 117, 1073) generated (+)-pleuromutilin (1). (+)-12-epi-Pleuromutilin and (+)-11,12-di-epi-pleuromutilin were prepared by related sequences. This work establishes a convergent entry to the pleuromutilins and provides a foundation for the production of novel antibiotics to treat drug-resistant and Gram-negative infections.


Subject(s)
Ketones/chemical synthesis , Polycyclic Compounds/chemical synthesis , Diterpenes/chemical synthesis , Diterpenes/chemistry , Ketones/chemistry , Molecular Conformation , Pleurotus/chemistry , Polycyclic Compounds/chemistry , Stereoisomerism , Pleuromutilins
3.
Org Lett ; 19(18): 4980-4983, 2017 09 15.
Article in English | MEDLINE | ID: mdl-28858512

ABSTRACT

An improved synthesis of an eneimide, which is a useful precursor to pleuromutilin-based antibiotics, is reported. This synthesis proceeds in six steps and 17% overall yield (27% based on recovery of a key hydrindenone intermediate) and requires two fewer chromatography steps and five fewer days of reaction time than the previously reported route. The use of expensive, acutely toxic, and precious metal reagents or catalysts has been minimized.


Subject(s)
Anti-Bacterial Agents/chemistry , Catalysis , Diterpenes , Molecular Structure , Polycyclic Compounds , Pleuromutilins
4.
Science ; 356(6341): 956-959, 2017 06 02.
Article in English | MEDLINE | ID: mdl-28572392

ABSTRACT

The tricyclic diterpene fungal metabolite (+)-pleuromutilin has served as a starting point for antibiotic development. Semisynthetic modification of its glycolic acid subunit at C14 provided the first analogs fit for human use, and derivatization at C12 led to 12-epi-pleuromutilins with extended-spectrum antibacterial activity, including activity against Gram-negative pathogens. Given the inherent limitations of semisynthesis, however, accessing derivatives of (+)-pleuromutilin with full control over their structure presents an opportunity to develop derivatives with improved antibacterial activities. Here we disclose a modular synthesis of pleuromutilins by the convergent union of an enimide with a bifunctional iodoether. We illustrate our approach through synthesis of (+)-12-epi-mutilin, (+)-11,12-di-epi-mutilin, (+)-12-epi-pleuromutilin, (+)-11,12-di-epi-pleuromutilin, and (+)-pleuromutilin itself in 17 to 20 steps.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Drug Design , Anti-Bacterial Agents/chemistry , Diterpenes/chemical synthesis , Diterpenes/chemistry , Molecular Structure , Polycyclic Compounds , Structure-Activity Relationship , Pleuromutilins
5.
Org Lett ; 18(19): 4880-4883, 2016 10 07.
Article in English | MEDLINE | ID: mdl-27670226

ABSTRACT

A general strategy for conjugate addition-C-acylation that enables the synthesis of enantioenriched ß-dicarbonyl compounds is described. A novel method for derivatizing these adducts by stereo- and site-selective zinc-catalyzed addition of alkyllithium reagents is also reported. These reactions can be performed in tandem to achieve an enantio- and diastereoselective four-component coupling. The in situ generation of weakly basic lithium zincate species is central to the success of all three transformations.


Subject(s)
Chemistry Techniques, Synthetic/methods , Ketones/chemical synthesis , Organometallic Compounds/chemistry , Zinc/chemistry , Acylation , Catalysis , Cycloaddition Reaction , Ketones/chemistry , Molecular Structure , Stereoisomerism
6.
J Org Chem ; 80(17): 8604-18, 2015 Sep 04.
Article in English | MEDLINE | ID: mdl-26203776

ABSTRACT

The half-sandwich ruthenium complexes 1-3 activate terminal alkynes toward anti-Markovnikov hydration and reductive hydration under mild conditions. These reactions are believed to proceed via addition of water to metal vinylidene intermediates (4). The functionalization of propargylic alcohols by metal vinylidene pathways is challenging owing to decomposition of the starting material and catalytic intermediates. Here we show that catalyst 2 can be employed to convert propargylic alcohols to 1,3-diols in high yield and with retention of stereochemistry at the propargylic position. The method is also amenable to propargylic amine derivatives, thereby establishing a route to enantioenriched 1,3-amino alcohol products. We also report the development of formal anti-Markovnikov reductive amination and oxidative hydration reactions to access linear amines and carboxylic acids, respectively, from terminal alkynes. This chemistry expands the scope of products that can be prepared from terminal alkynes by practical and high-yielding metal-catalyzed methods.

7.
Angew Chem Int Ed Engl ; 53(30): 7892-5, 2014 Jul 21.
Article in English | MEDLINE | ID: mdl-24964738

ABSTRACT

Anti-Markovnikov alkyne hydration provides a valuable route to aldehydes. Half-sandwich ruthenium complexes ligated by 5,5'-bis(trifluoromethyl)-2,2'-bipyridine are remarkably active for this transformation. In the presence of 2 mol % metal, a wide range of functionalized aliphatic and aromatic alkynes are hydrated in high yield at ambient temperature.

8.
J Am Chem Soc ; 136(19): 7058-67, 2014 May 14.
Article in English | MEDLINE | ID: mdl-24786693

ABSTRACT

The conversion of terminal alkynes to functionalized products by the direct addition of heteroatom-based nucleophiles is an important aim in catalysis. We report the design, synthesis, and mechanistic studies of the half-sandwich ruthenium complex 12, which is a highly active catalyst for the anti-Markovnikov reductive hydration of alkynes. The key design element of 12 involves a tridentate nitrogen-based ligand that contains a hemilabile 3-(dimethylamino)propyl substituent. Under neutral conditions, the dimethylamino substituent coordinates to the ruthenium center to generate an air-stable, 18-electron, κ(3)-complex. Mechanistic studies show that the dimethylamino substituent is partially dissociated from the ruthenium center (by protonation) in the reaction media, thereby generating a vacant coordination site for catalysis. These studies also show that this substituent increases hydrogenation activity by promoting activation of the reductant. At least three catalytic cycles, involving the decarboxylation of formic acid, hydration of the alkyne, and hydrogenation of the intermediate aldehyde, operate concurrently in reactions mediated by 12. A wide array of terminal alkynes are efficiently processed to linear alcohols using as little as 2 mol % of 12 at ambient temperature, and the complex 12 is stable for at least two weeks under air. The studies outlined herein establish 12 as the most active and practical catalyst for anti-Markovnikov reductive hydration discovered to date, define the structural parameters of 12 underlying its activity and stability, and delineate design strategies for synthesis of other multifunctional catalysts.

9.
Neuron ; 76(2): 410-22, 2012 Oct 18.
Article in English | MEDLINE | ID: mdl-23083742

ABSTRACT

Neuroligin (NLG), a postsynaptic adhesion molecule, is involved in the formation of synapses by binding to a cognate presynaptic ligand, neurexin. Here we report that neuroligin-1 (NLG1) undergoes ectodomain shedding at the juxtamembrane stalk region to generate a secreted form of NLG1 and a membrane-tethered C-terminal fragment (CTF) in adult rat brains in vivo as well as in neuronal cultures. Pharmacological and genetic studies identified ADAM10 as the major protease responsible for NLG1 shedding, the latter being augmented by synaptic NMDA receptor activation or interaction with soluble neurexin ligands. NLG1-CTF was subsequently cleaved by presenilin/γ-secretase. Secretion of soluble NLG1 was significantly upregulated under a prolonged epileptic seizure condition, and inhibition of NLG1 shedding led to an increase in numbers of dendritic spines in neuronal cultures. Collectively, neuronal activity-dependent proteolytic processing of NLG1 may negatively regulate the remodeling of spines at excitatory synapses.


Subject(s)
Cell Adhesion Molecules, Neuronal/metabolism , Proteolysis , ADAM Proteins/deficiency , ADAM10 Protein , Amyloid Precursor Protein Secretases/deficiency , Amyloid Precursor Protein Secretases/metabolism , Animals , Animals, Newborn , Biotinylation , Calcium-Binding Proteins , Cell Adhesion Molecules, Neuronal/genetics , Cells, Cultured , Cerebellum/metabolism , Dendritic Spines/metabolism , Dipeptides/pharmacology , Disease Models, Animal , Embryo, Mammalian , Enzyme Inhibitors/pharmacology , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Hippocampus/cytology , Humans , Male , Membrane Proteins/deficiency , Mice , Mice, Inbred BALB C , Mice, Knockout , Muscarinic Agonists/toxicity , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neural Cell Adhesion Molecules/metabolism , Neurons/ultrastructure , Organ Culture Techniques , Pilocarpine/toxicity , RNA Interference/physiology , Rats , Rats, Wistar , Status Epilepticus/chemically induced , Status Epilepticus/metabolism , Status Epilepticus/pathology , Synaptosomes/drug effects , Synaptosomes/metabolism , Transfection
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