A Multidimensional Diversity‐Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles
نویسندگان
چکیده
Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity-oriented synthesis, and its application towards macrocycles. This enabled the step-efficient generation of a library of 45 novel, structurally diverse, and highly-functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza-ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecular shape.
منابع مشابه
A novel complexity-to-diversity strategy for the diversity-oriented synthesis of structurally diverse and complex macrocycles from quinine.
Recent years have witnessed a global decline in the productivity and advancement of the pharmaceutical industry. A major contributing factor to this is the downturn in drug discovery successes. This can be attributed to the lack of structural (particularly scaffold) diversity and structural complexity exhibited by current small molecule screening collections. Macrocycles have been shown to exhi...
متن کاملA Novel Strategy of Ugi-4CR/Huisgen 1,3-Dipolar Synthesis of 1H-1,2,3-Triazole-Modified Peptidoimetics
In this protocol, we report a novel approach for the synthesis of a new class of heterocyclic 1H-1,2,3-triazole-modified peptidomimetic compounds. The process consists of an Ugi four-component condensation reaction of amines, an isocyanide, an aldehyde and acids followed by a Huisgen 1,3-dipolar cycloaddition reaction with an azide group in the presence of a catalytic amount of CuSO4</...
متن کاملDiversity-Oriented Synthesis Approach to Macrocycles via Oxidative Ring Expansion
Macrocycles are key structural elements in numerous bioactive small molecules and are attractive targets in the diversity-oriented synthesis of natural product-based libraries. However, efficient and systematic access to diverse collections of macrocycles has proven difficult using classical macrocyclization reactions. To address this problem, we have developed a concise, modular approach to th...
متن کاملA one-bead, one-stock solution approach to chemical genetics: part 1.
BACKGROUND In chemical genetics, small molecules instead of genetic mutations are used to modulate the functions of proteins rapidly and conditionally, thereby allowing many biological processes to be explored. This approach requires the identification of compounds that regulate pathways and bind to proteins with high specificity. Structurally complex and diverse small molecules can be prepared...
متن کاملA practical and efficient approach to imidazo[1,2-a]pyridine-fused isoquinolines through the post-GBB transformation strategy
Diversity-oriented synthesis of the biologically intriguing imidazo[1,2-a]pyridine-fused isoquinoline systems from readily available starting materials was achieved through the Groebke-Blackburn-Bienaymé reaction followed by a gold-catalyzed cyclization strategy. The synthetic approach is characterized by mild reaction conditions and a broad substrate scope, allowing for the rapid construction ...
متن کامل