Combinatorial Chemistry Advanced Medicinal Chemistry (Pharm 5219): Section A Ref.: An Introduction to Medicinal Chemistry, 3 rd ed. 2005, G.L.Patrick, Oxford University press Md. Saifuzzaman Assoc. Professor

Combinatorial synthesis A means of producing a large number of compounds in short period of time, using a defined reaction route and a large variety of starting materials and reagents. Combinatorial chemistry is an approach providing efficient synthesis of large collection of molecules & screening of libraries of related compounds to isolate molecule of desirable property.

Combinatorial synthesis Done on a very small scale Using solid phase synthesis Automated or semi-automated process Each reaction in several reaction vessels at the same time and under identical condition, using different reagents in each vessel. When single product is obtained in each vessel – parallel synthesis When mixtures of compounds are produced – mixed synthesis

Why needed? M. chemistry requires – rapid synthesis of large no. of compounds. Major driving force (old)– need to find new lead compounds. At present, an explosion in no. of new drug targets developed by proteomics & genomics. With huge new targets, there is a problem of identifying function of targets and finding lead compounds interacting to them. Driving force (now) – discovery of new drug targets.

Why needed? To find a lead compound – lead discovery program for 100 targets & screen over 1 million compounds per year (avg. works in a pharma company). Com. chem. provides a means of producing that many compounds.

Combinatorial synthesis in drug discovery & drug optimization Find a target Find a lead Isolate active structure Identify structure SAROptimize lead Combinatorial synthesis

How used? Both parallel & mixed syntheses – can be used But mixed synthesis – generate more structure & increase chance of finding a lead compound. Mixtures of compounds – produced in each reaction flask (thousands or even millions of novel structures vs few dozen by conventional means).

How used? Mixtures of compounds in a reaction vessel – tested for biological activity. If negative, no need to study that mixture & stored. If positive, identify which component is active compound. That saves effort of synthesizing, purifying and identifying each components of that mixture.

Mixed combinatorial synthesis: equivalent of nature’s chemical pool Through evolution, nature has produced a huge number & variety of chemical structures, some biologically active. Traditionally, active principles – picked up from that pool and developed. Mixed combinatorial synthesis – pools of purely synthetic structures – pick up active compounds. Diversity is less but isolating, purifying and identifying new agents is faster.

Parallel synthesis in SAR & drug optimization Each compound has to be tested individually. Though more compounds by mixed synthesis, time saved in producing them lost in separation & identification. Parallel synthesis is more common than mixed synthesis in Ph. Industry.

Advantages of Combinatorial Synthesis Perform fewer reactions and fewer tests to identify the biological activity of a “winning” molecule Use synthetic organic chemistry to generate many compounds in a single or parallel batch

Synthesis of Fruity Esters Assigned Problem Use combinatorial chemistry to synthesize an ester of an assigned scent.

CH 3 OHA1 CH 3 CH 2 OHA2 1-pentanolA3 3-methylbutanol A4 1-octanol A5 Butanoic acidC1 Propanoic acidC2 Acetic acidC3 Generation of library of molecules Mix combinations of alcohols and carboxylic acids to solve the assigned problem Possible combinations – A1C1, A1C2, A1C3……. Deconvolution of library – checking the odor of esters

Preparation of Hydrazones and Discovery of an Antibiotic Compound using Combinatorial techniques Synthesis of Hydrazones

A1-B1 A2-B1 A3-B1 A1-B2 A2-B2 A3-B2 A1-B3 A2-B3 A3-B3 Generation of Libraries

Solid phase techniques Combinatorial experiments….. Few - in solution Majority - using solid phase techniques

Solid phase techniques Advantages of solid phase techniques 1.Different starting materials - bound to separate beads – mixed together – treated with another reagent as a single experiment. Starting materials & products – still physically distinct. 2.Excess reagents and unbound by-products – can be removed by washing the resin. 3.Large excesses of reagents – can be used to drive the reactions to completion (≥ 99%). 4.If low loadings (≤ 0.8 mmol/g support), undesired side effects (e.g., cross-linking) can be suppressed.

Solid phase techniques Advantages of solid phase techniques….. 5.Intermediates – bound to the bead, so no need to purify. 6.Individual beads – separated at the end to yield individual products. 7.Polymeric support – regenerated & reused if appropriate cleavage conditions and suitable anchor/linker groups. 8.Automation possible.

Solid phase techniques Essential requirements for solid phase synthesis A cross-linked insoluble polymeric support – inert to reaction conditions (e.g., a resin bead). An anchor/linker covalently linked to resin – with a reactive functional group (i.e., substrates can attach to it). A bond linking substance to linker – stable to reaction conditions used in synthesis. A means of cleaving products or intermediates from linker. Protection of functional groups not involved in synthesis.