Function through Synthesis-Informed Design

• Published in: Accounts of chemical research 2015-03, Vol.48 (3), p.752-760
• Main Authors: Wender, Paul A, Quiroz, Ryan V, Stevens, Matthew C
• Format: Article
• Language: English
• Subjects: Animals; Biological Products - chemical synthesis; Biological Products - chemistry; Biological Products - pharmacology; Bryostatins - chemical synthesis; Bryostatins - chemistry; Bryostatins - pharmacology; Design engineering; DNA Cleavage; Drug Delivery Systems; Drug Design; Economics; Humans; Kinases; Ligands; Mathematical analysis; Mathematical models; Organic Chemicals - chemical synthesis; Organic Chemicals - chemistry; Organic Chemicals - pharmacology; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Strategy; Synthesis; Synthesis (chemistry)
• ISSN: 0001-4842; 1520-4898
• DOI: 10.1021/acs.accounts.5b00004

In 1996, a snapshot of the field of synthesis was provided by many of its thought leaders in a Chemical Reviews thematic issue on “Frontiers in Organic Synthesis”. This Accounts of Chemical Research thematic issue on “Synthesis, Design, and Molecular Function” is intended to provide further perspective now from well into the 21st century. Much has happened in the past few decades. The targets, methods, strategies, reagents, procedures, goals, funding, practices, and practitioners of synthesis have changed, some in dramatic ways as documented in impressive contributions to this issue. However, a constant for most synthesis studies continues to be the goal of achieving function with synthetic economy. Whether in the form of new catalysts, reagents, therapeutic leads, diagnostics, drug delivery systems, imaging agents, sensors, materials, energy generation and storage systems, bioremediation strategies, or molecules that challenge old theories or test new ones, the function of a target has been and continues to be a major and compelling justification for its synthesis. While the targets of synthesis have historically been heavily represented by natural products, increasingly design, often inspired by natural structures, is providing a new source of target structures exhibiting new or natural functions and new or natural synthetic challenges. Complementing isolation and screening approaches to new target identification, design enables one to create targets de novo with an emphasis on sought-after function and synthetic innovation with step-economy. Design provides choice. It allows one to determine how close a synthesis will come to the ideal synthesis and how close a structure will come to the ideal function. In this Account, we address studies in our laboratory on function-oriented synthesis (FOS), a strategy to achieve function by design and with synthetic economy. By starting with function rather than structure, FOS places an initial emphasis on target design, thereby harnessing the power of chemists and computers to create new structures with desired functions that could be prepared in a simple, safe, economical, and green, if not ideal, fashion. Reported herein are examples of FOS associated with (a) molecular recognition, leading to the first designed phorbol-inspired protein kinase C regulatory ligands, the first designed bryostatin analogs, the newest bryologs, and a new family of designed kinase inhibitors, (b) target modification, leading to highly