Allenes and Transition Metals:  A Diverging Approach to Heterocycles

Brummond, Kay M.; Mitasev, Branko

doi:10.1021/ol0492391

Cited by 94 publications

(60 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1). For example, reaction of allene-yne 1 with molybdenum hexacarbonyl [MoðCOÞ 6 ] affords alkylidene cyclopentenone 2 by a selective reaction with the proximal double bond of the allene (8). Alternatively, reaction of the allene-yne 1 with 5 mol% of rhodium biscarbonyl chloride dimer ½RhðCOÞ 2 Cl 2 under a carbon monoxide atmosphere gives the 4-alkylidene cyclopentenone 3 via a selective cyclocarbonylation reaction with the distal double bond of the allene.…”

Section: Resultsmentioning

confidence: 99%

Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators

Huryn

Brodsky

Brummond

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Unique chemical methodology enables the synthesis of innovative and diverse scaffolds and chemotypes and allows access to previously unexplored "chemical space." Compound collections based on such new synthetic methods can provide small-molecule probes of proteins and/or pathways whose functions are not fully understood. We describe the identification, characterization, and evolution of two such probes. In one example, a pathway-based screen for DNA damage checkpoint inhibitors identified a compound, MARPIN (ATM and ATR pathway inhibitor) that sensitizes p53-deficient cells to DNA-damaging agents. Modification of the small molecule and generation of an immobilized probe were used to selectively bind putative protein target(s) responsible for the observed activity. The second example describes a focused library approach that relied on tandem multicomponent reaction methodologies to afford a series of modulators of the heat shock protein 70 (Hsp70) molecular chaperone. The synthesis of libraries based on the structure of MAL3-101 generated a collection of chemotypes, each modulating Hsp70 function, but exhibiting divergent pharmacological activities. For example, probes that compromise the replication of a disease-associated polyomavirus were identified. These projects highlight the importance of chemical methodology development as a source of small-molecule probes and as a drug discovery starting point.ATPase | diversity oriented synthesis | isosteres | UPCMLD | alpha-methylene cyclopentenone

show abstract

Section: Resultsmentioning

confidence: 99%

Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators

Huryn

Brodsky

Brummond

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…38 Nielsen e Schreiber identificaram uma estratégia comum a muitos dos processos de síntese orientada pela diversidade estrutural, a qual eles chamaram de construir/acoplar/parear. 40,41 Nos últimos anos alguns trabalhos têm sido desenvolvidos combinando o conceito de síntese orientada pela diversidade estrutural com o conceito de estruturas privilegiadas. Esta estratégia se baseia no fato de que algumas classes de esqueletos moleculares (estruturas privilegiadas) são capazes de atuar como ligantes para diversos receptores biológicos, devido às suas propriedades físico-químicas favoráveis.…”

Section: Esquema 5 Estratégia Para a Geração Dos Compostos Macrocíclunclassified

Synthetic Strategies in Drug Discovery: Employng Diversity-Oriented Synthesis

Sangi¹

2016

Química Nova

View full text Add to dashboard Cite

publicado na web em 25/05/2016 SYNTHETIC STRATEGIES IN DRUG DISCOVERY: EMPLOYNG DIVERSITY-ORIENTED SYNTHESIS. Drug discovery often involves screening synthetic small molecules for their ability to bind to a macromolecular target. Target-Oriented Synthesis of a specific compound or a focused library can be planned combining retrosynthetic analysis and rational drug design. Biologically active molecules also can be identified through the unfocused screening of compound libraries. Diversity-Oriented Synthesis (DOS) emerges as an excellent strategy that leads to a library of structurally complex and diverse small molecules, covering a larger chemical space and increasing the probability of identifying modulators.Keywords: target oriented synthesis; diversity oriented synthesis; drug discovery. INTRODUÇÃOAntes do desenvolvimento da síntese orgânica, a obtenção de substâncias orgânicas para os seus diversos fins, inclusive terapêuti-cos, era feita por processos de fermentação ou isolamento de fontes naturais. Devido a sua ampla diversidade estrutural e funcional, muitos compostos de origem natural são usados no tratamento de diversos males e desordens biológicas.Por anos, a maioria dos fármacos disponíveis no mercado eram produtos naturais ou mesmo análogos inspirados neles, alguns obtidos por modificação estrutural outros por síntese total, quando a fonte natural não supria a demanda. 1,2Os produtos naturais bioativos geralmente são isolados em baixas quantidades, e muitas vezes apresentam alta complexidade estrutural, contendo vários centros estereogênicos. A complexidade destes compostos dificulta muito a sua obtenção através de métodos sintéticos rápidos e a baixa disponibilidade inviabiliza o seu emprego em High-Throughput Screening (HTS).Portanto, a busca por lucros mais rápidos por parte das indústrias farmacêuticas aliada ao grande desenvolvimento dos métodos de síntese orgânica fez com que os produtos naturais deixassem de ser a maior fonte de novos fármacos, sendo substituídos por compostos sintéticos. 1A identificação das funções biológicas, o isolamento e determinação estrutural de muitas macromoléculas e de seus ligantes naturais têm permitido o planejamento racional de moduladores destes novos alvos macromoleculares. Desta forma, a síntese de coleções focadas empregando a química combinatória emergiu como uma das principais ferramentas na busca por novos fármacos.Nas últimas décadas a área de síntese orgânica passou por uma grande evolução 3 . O número e a complexidade dos novos compostos sintetizados aumentaram drasticamente, e dentre estes novos compostos pode-se incluir um grande número de fármacos e candidatos, além de muitos reagentes usados para explorar processos biológicos de várias formas.Atualmente, a síntese de compostos orgânicos constitui uma importante parte no processo de descoberta e desenvolvimento de novos fármacos. Na busca por um fármaco que tenha como alvo uma macromolécula biológica, anteriormente selecionada, é comum fazer uso da estratégia de síntese orientada pelo alvo, seja com ...

show abstract

“…Our group previously demonstrated that various reaction topologies could be controlled by a proper choice of the transition metal catalyst, as well as the functionalization of the starting enyne (7-10). Significant advances in this area can now enable incorporation of such transformations into synthetic strategies for the assembly of skeletally diverse chemical libraries (11)(12)(13)(14)(15)(16)(17)(18). However, several challenges remain to be addressed to facilitate access to high-diversity chemical libraries.…”

mentioning

confidence: 99%

Creation and manipulation of common functional groups en route to a skeletally diverse chemical library

Cui

Hao

Ulanovskaya

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We have developed an efficient strategy to a skeletally diverse chemical library, which entailed a sequence of enyne cycloisomerization, [4 þ 2] cycloaddition, alkene dihydroxylation, and diol carbamylation. Using this approach, only 16 readily available building blocks were needed to produce a representative 191-member library, which displayed broad distribution of molecular shapes and excellent physicochemical properties. This library further enabled identification of a small molecule, which effectively suppressed glycolytic production of ATP and lactate in CHO-K1 cell line, representing a potential lead for the development of a new class of glycolytic inhibitors.diversity-oriented synthesis | glycolysis | skeletal diversity S tructurally diverse collections of small molecules provide a validated source of chemical probes for basic and translational biomedical research (1, 2). Variation of the scaffold architecture of such compound libraries is particularly desirable to enable identification of new bioactive chemical probes with higher probability and greater efficiency. High-throughput synthesis of skeletally diverse small-molecule libraries represents one of the most challenging aspects of diversity-oriented synthesis and requires identification of efficient reaction sequences that can rapidly convert a small subset of readily available compounds to a large number of skeletally diverse chemical entities for subsequent biomedical applications (3).Transition metal-catalyzed cycloisomerization of enynes represents a powerful method for structural diversification (4-6). Our group previously demonstrated that various reaction topologies could be controlled by a proper choice of the transition metal catalyst, as well as the functionalization of the starting enyne (7-10). Significant advances in this area can now enable incorporation of such transformations into synthetic strategies for the assembly of skeletally diverse chemical libraries (11)(12)(13)(14)(15)(16)(17)(18). However, several challenges remain to be addressed to facilitate access to high-diversity chemical libraries. Typically, multiple cycloisomerization precursors are manually assembled to yield different skeletal frameworks upon their cycloisomerizations. A smaller number of building blocks would minimize this laborious process and increase efficiency. Another limitation is the difficulty of subsequent diversification of cycloisomerization products, which is complicated by the lack of common functional groups and variable chemical reactivity of such compounds. Ideally, the cycloisomerization should provide access to products containing the same functional group to enable the next diversity-generating step, which should yield another common functional group. If such common and reactive functional groups are efficiently produced at every stage of the synthesis, this synthetic pathway can readily provide access to a structurally diverse library starting with only a small set of building blocks.We describe the development of a unique approach, which ha...

show abstract

Allenes and Transition Metals: A Diverging Approach to Heterocycles

Cited by 94 publications

References 7 publications

Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators

Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators

Synthetic Strategies in Drug Discovery: Employng Diversity-Oriented Synthesis

Creation and manipulation of common functional groups en route to a skeletally diverse chemical library

Contact Info

Product

Resources

About