Synthetic Macrocycles for Drug Development via Modular Assembly
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Solution Overview
Problem
Macrocyclic natural and synthetic products face limitations in drug development due to high structural complexity, low metabolic stability, low oral bioavailability, low membrane permeability, short half-life, complex chemical synthesis, and high production costs, which hinder their effectiveness as drug candidates.
Innovation Solution
Development of novel, fully synthetic macrocyclic compounds of type Ia/Ib, synthesized through a modular approach using protected divalent phenol or thiophenol derivatives as conformation-inducing templates, connected via ether or thioether bonds, with tertiary amines as conformational modulators, and amino acid-derived subunits, enhancing conformational stability and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If macrocyclic natural and synthetic products are used as drug candidates, then remarkable biological activities are achieved, but high structural complexity and complex chemical synthesis arise
Solution Approach 1:
The macrocyclic compounds are synthesized through a modular approach using building blocks A, B, and C that can be independently designed and assembled. This segmentation allows complex macrocyclic structures to be constructed from simpler, standardized components, reducing synthesis complexity while maintaining biological activity.
Solution Approach 2:
Building blocks A and B are pre-designed with specific conformational constraints and properties before assembly into the final macrocyclic structure. This preliminary preparation of functional modules enables more efficient and less complex synthesis of the complete macrocyclic compound while ensuring desired biological properties.
2Reliability
If macrocyclic natural and synthetic products are used as drug candidates, then remarkable biological activities are achieved, but low metabolic stability and short half-life occur
Solution Approach 1:
Specific regions of the macrocyclic structure (building blocks A, B, and C) are optimized with distinct chemical properties to enhance metabolic stability. The conformational constraints in these local regions protect against metabolic degradation while preserving the overall biological activity of the macrocyclic compound.
3Reliability
If macrocyclic natural and synthetic products are used as drug candidates, then remarkable biological activities are achieved, but low oral bioavailability and low membrane permeability occur
Solution Approach 1:
The conformational constraints and chemical composition of building blocks A, B, and C are optimized to modify physical-chemical parameters such as solubility and membrane permeability. These parameter changes enhance oral bioavailability while maintaining the biological activity required for therapeutic effect.
Data Source
Figure 1A~1C
Figure 2~3
AI summary
Conformationally restricted, spatially defined 12-30 membered macrocyclic ring systems of formulae Ia and Ib are constituted by three distinct molecular parts: Template A, conformation Modulator B and Bridge C. These macrocycles Ia and Ib are readily manufactured by parallel synthesis or combinatorial chemistry in solution or on solid phase. They are designed to interact with a variety of specific biological target classes, examples being the agonistic or antagonistic activity on G-protein coupled receptors (GPCRs), ion channels and signal transduction pathways. In particular, these macrocycles act as antagonists of the motilin receptor, the FP receptor and the purinergic receptors P2Y1, as modulators of the serotonin receptor of subtype 5-HT2B, as blockers of the voltage-gated potassium channel Kv1.3 and as inhibitors of the β-catenin-dependent "canonical" Wnt pathway. Thus they are showing great potential as medicaments for a variety of diseases.