ABSTRACT
In the context of a PRMT5 inhibitor program, we describe our efforts to develop a flexible and robust strategy to access tetrahydrofuro[3,4-b]furan nucleoside analogues. Ultimately, it was found that a Wolfe type carboetherification from an alkenol derived from d-glucofuranose diacetonide was capable of furnishing the B-ring and installing the desired heteroaryl group in a single step. Using this approach, key intermediate 1.3-A was delivered on a gram scale in a 62% yield and 9.1:1 dr in favor of the desired S-isomer. After deprotection of 1.3-A, a late-stage glycosylation was performed under Mitsunobu conditions to install the pyrrolopyrimidine base. This provided serviceable yields of nucleoside analogues in the range of 31-48% yield. Compound 1.1-C was profiled in biochemical and cellular assays and was demonstrated to be a potent and cellularly active PRMT5 inhibitor, with a PRMT5-MEP50 biochemical IC50 of 0.8 nM, a MCF-7 target engagement EC50 of 3 nM, and a Z138 cell proliferation EC50 of 15 nM. This work sets the stage for the development of new inhibitors of PRMT5 and novel nucleoside chemical matter for alternate drug discovery programs.
Subject(s)
Nucleosides , Protein-Arginine N-Methyltransferases , Cell Proliferation , Enzyme Inhibitors , FuransABSTRACT
The polyketide, 20-deoxy elansolid B1, was prepared by a convergent strategy that relied on a putative biomimetic intramolecular Diels-Alder cycloaddition (IMDA) via a vinylic p-quinone methide intermediate to furnish the key tetrahydroindane unit. The (Z,E,Z)-configured triene unit was constructed by Pd-catalyzed Suzuki-Miyaura and Stille cross-coupling reactions without isomerization of any of the olefinic double bonds. Formation of a p-methide quinone intermediate under basic conditions and subsequent Michael addition by water to this intermediate proceeded with high facial selectivity which terminated this total synthesis. Remarkably, the new elansolid derivative 2 c shows very good inhibitory effect against Bacillus subtilis and Staphylococcus aureus (including MRSA) similarly to the best elansolid derivatives reported so far. Consequently, the hydroxyl group at C20 is not essential for antibacterial activity.
Subject(s)
Alkenes/chemistry , Anti-Bacterial Agents/chemical synthesis , Indolequinones/chemistry , Indolequinones/chemical synthesis , Macrolides/chemical synthesis , Anti-Bacterial Agents/chemistry , Biomimetics , Catalysis , Cycloaddition Reaction , Macrolides/chemistry , Staphylococcus aureusABSTRACT
A combination of mutasynthesis using a mutant strain of A. pretiosum blocked in the biosynthesis of amino-hydroxybenzoic acid (AHBA) and semisynthesis relying on a Stille cross-coupling step provided access to new ansamitocin derivatives of which one was attached by a thermolabile linker to nanostructured iron oxide particles. When exposed to an oscillating electromagnetic field the resulting iron oxide/ansamitocin conjugate 19 heats up in an aqueous suspension and the ansamitocin derivative 16 is released by means of a retro-Diels-Alder reaction. It exerts strong antiproliferative activity (IC50 =4.8â ng mg-1 ) in mouse fibroblasts. These new types of conjugates have the potential for combating cancer through hyperthermia and chemotherapy using an electromagnetic external trigger.
Subject(s)
Ferric Compounds/chemistry , Magnetite Nanoparticles/chemistry , Maytansine/analogs & derivatives , Animals , Cell Line, Tumor , Cell Survival/drug effects , Cycloaddition Reaction , Hydroxybenzoates/chemical synthesis , Hydroxybenzoates/chemistry , Hydroxybenzoates/toxicity , Magnetite Nanoparticles/toxicity , Maytansine/chemistry , MiceABSTRACT
This conceptual review examines the ideal multistep synthesis from the perspective of nature. We suggest that besides step- and redox economies, one other key to efficiency is steady state processing with intermediates that are immediately transformed to the next intermediate when formed. We discuss four of nature's strategies (multicatalysis, domino reactions, iteration and compartmentation) that commonly proceed via short-lived intermediates and show that these strategies are also part of the chemist's portfolio. We particularly focus on compartmentation which in nature is found microscopically within cells (organelles) and between cells and on a molecular level on multiprotein scaffolds (e.g. in polyketide synthases) and demonstrate how compartmentation is manifested in modern multistep flow synthesis.
Subject(s)
Biological Products/chemical synthesis , Biological Products/chemistry , Biological Products/pharmacology , Molecular Structure , Oxidation-Reduction , Polyketides/metabolismABSTRACT
A general and high yielding annulation strategy for the synthesis of various carbo- and heterocycles, based on an intramolecular aryne ene reaction is described. It was found that the geometry of the olefin is crucial to the success of the reaction, with exclusive migration of the trans-allylic-H taking place. Furthermore, the electronic nature of the aryne was found to be important to the success of the reaction. Deuterium labeling studies and DFT calculations provided insight into the reaction mechanism. The data suggests a concerted asynchronous transition state, resembling a nucleophilic attack on the aryne. This strategy was successfully applied to the formal synthesis of the ethanophenanthridine alkaloid (±)-crinine.
Subject(s)
Amaryllidaceae Alkaloids/chemistry , Amaryllidaceae Alkaloids/chemical synthesis , Models, Molecular , StereoisomerismABSTRACT
Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp3-sp2 cross-coupling technologies. This resulted in the discovery of a unique sp3-rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound, 25, demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.
Subject(s)
Parkinson Disease , Rats , Humans , Animals , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Parkinson Disease/drug therapy , Indazoles/pharmacology , Indazoles/therapeutic use , Leukocytes, Mononuclear/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemistry , Brain/metabolism , Adenosine TriphosphateABSTRACT
Although the chemistry of arynes is well developed, some challenges still remain. The ene reaction of arynes has not gained widespread use in synthesis as a result of poor yields and selectivity. A general, high yielding and selective intramolecular aryne-ene reaction is described providing various benzofused carbo- and heterocycles. Mechanistic data is presented, and a rationale for the resulting stereochemistry is discussed.
Subject(s)
Organic Chemicals/chemical synthesis , Organic Chemicals/chemistryABSTRACT
Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo, supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure-activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising in vitro profiles.
ABSTRACT
They all fall down: The value of domino processes can be greatly enhanced when the possibility exists for one to selectively diverge from a common intermediate. In preliminary studies the dual reactivity of aryl-palladium intermediates is exploited. A diverse array of fluorene and phenanthrene derivatives were synthesized in a rapid and efficient manner (see scheme).
Subject(s)
Fluorenes/chemistry , Palladium/chemistry , Phenanthrenes/chemistry , Catalysis , Fluorenes/chemical synthesis , Phenanthrenes/chemical synthesis , StereoisomerismABSTRACT
High yielding, room temperature cross couplings of unactivated alkyl bromides and aryl bromides/chlorides with alkyl-9-BBN reagents has been achieved using an NHC-based catalyst (Pd-PEPPSI-IPr) via a general, functional-group tolerant and easily implemented protocol.
ABSTRACT
The use of aryl triflates as reaction partners in a palladium-catalyzed domino direct arylation/N-arylation provides a great advantage due to the availability of starting materials. Furthermore, it allows expedient access to biologically interesting benzo[c]phenanthridine alkaloids.
Subject(s)
Alkaloids/chemical synthesis , Benzophenanthridines/chemical synthesis , Mesylates/chemistry , Palladium/chemistry , Alkaloids/chemistry , Benzophenanthridines/chemistry , Catalysis , Combinatorial Chemistry Techniques , Molecular StructureABSTRACT
The highly strained 2H-azirine ring system has been the source of considerable theoretical and synthetic work. The reaction of these strained heterocycles with transition metals has been documented to give rise to ring opening and subsequent formation of varied heterocycles. An interesting domino reaction is described wherein the strained bicyclic alkene, norbornene, mediates the reaction of 2H-azirines with aryl iodides under palladium catalysis to provide indole or polycyclic dihydroimidazole heterocycles.
Subject(s)
Azirines/chemistry , Hydrocarbons, Iodinated/chemistry , Indoles/chemical synthesis , Palladium/chemistry , Catalysis , Combinatorial Chemistry Techniques , Imidazoles/chemical synthesis , Imidazoles/chemistry , Indoles/chemistry , Molecular StructureABSTRACT
A palladium-catalyzed crossed biaryl coupling/reduction sequence enables the formation of meta-substituted biaryls via solvent-mediated arylpalladium(II) reduction. Isotope labeling studies determined that the decomposition of 1,2-dimethoxyethane (DME) is indeed involved in the reductive process.