Notes on Combinatorial and Parallel Synthesis in Medicinal Chemistry

Combinatorial and Parallel Synthesis

• Purpose: Enable the production of multiple different compounds quickly using defined reaction routes.
• Method:
  • Reactions conducted on small scales.
  • Use of automation or semi-automation.

Historical Context in Medicinal Chemistry

• Past Approach:
  • Identifying a lead compound with useful activity.
  • Modifying the compound to develop clinically useful drugs.
• Current Approach:
  • Projects start with an identifiable biological target.
  • Mapping of the human genome reveals a vast number of unknown proteins.
  • Focus on creating lead compounds that interact effectively with targets.
  • Limitation primarily in finding an appropriate lead compound.

Impact of Modern Techniques

• Advancements:
  • Medicinal chemists can synthesize and screen thousands of structures rapidly.
  • Ability to identify structure-activity relationships.
  • Discovery of analogues with better activity and fewer side effects.

Solid-Phase Techniques

• Process:
  • Starting material is linked to a solid support (e.g., resin).
  • Reactions can be carried out sequentially on the attached molecule.
  • Final structure detached from the solid support.
• Advantages:
  • Large excess of reagents can drive reactions to completion.
  • Process amenable to automation.

Requirements for Solid-Phase Synthesis

• Materials:
  • Cross-linked insoluble polymeric support (e.g., resin bead) that is inert.
  • Anchor or linker covalently linked to the resin.
  • Method for cleaving the substrate from the linker.
  • Protecting groups for functional groups to prevent undesirable reactions.

Solid Phase Peptide Synthesis (SPPS)

• Focus: Utilizing Fmoc protecting group with a base (e.g., piperidine) for deprotection.

The Solid Support

• Resin Properties:
  • Must swell in solvent while remaining stable.
  • Most reactions occur in the interior rather than the surface of the bead.
  • Examples include Merrifield resin, Wang resin, TentaGel Resin.

The Anchor/Linker

• Definition:
  • A molecular unit covalently attached to the polymer chain.
• Selection Criteria: Depends on the desired chemical properties and application.

Other Examples of Solid-Phase Synthesis

• Expansion of Techniques:
  • Past success with peptide synthesis has led to methods for synthesizing small non-peptide molecules.
  • Focus on producing heterocyclic structures with better pharmacokinetic properties.

Compound Library

• Definition: Large quantities of compounds synthesized by solid-phase methods can be stored.
• Importance:
  • High structural diversity is crucial for successful leads.
  • Avoidance of libraries with many similar compounds.
• Scaffolds: Spider-like molecules with a central body (scaffold) and various arms (substituents) to probe binding sites.

Scaffolds and Diversity

• Structural Diversity:
  • Half of known drugs use only 32 different scaffolds.
  • Points to the ability to define "drug-like" molecules and design focused compound libraries by computer programs.

Parallel Synthesis

• Method:
  • Reactions in series of wells, each containing a single product.
  • Aimed at eliminating bottlenecks in synthesis, can be applied in solid-phase or solution-phase organic synthesis (SPOS).

Combinatorial Synthesis

• Definition:
  • Deliberately produce mixtures of compounds in each vessel.
  • Enables synthesis of a large number of novel structures.
  • Active compounds may be found within non-separated mixtures.
• Considerations:
  • Identifying active components can be complicated.
  • Potential for false positives in activity testing.
  • Negative assay results may occur due to unexpected reactions.

Mix and Split Method

• Process:
  • Structures synthesized on solid supports (e.g., beads) with different structures on different beads.
  • Beads mixed in a reaction vial to create mixtures of distinct structures, maximizing the diversity of compounds tested for activity.