Pyrrolobenzodiazepine Dimer Linkage via C1 Position
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Solution Overview
Problem
Previous attempts to link pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) dimers through the C-ring have been disappointing, with poor DNA binding results, particularly for C2 and C3 substitution, which affects their interaction in the minor groove.
Innovation Solution
A compound of formula (I) is developed, allowing for linkage through the C1 position, with optional double bonds between C1 and C2 or C2 and C3, and various substituents to form a bridge between monomers, enhancing DNA binding affinity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PBD dimers are linked through the C-ring (C2 or C3 position), then the structure allows for dimer formation, but the DNA binding affinity is poor
Solution Approach 1:
The patent changes the linkage position parameter from C2/C3 to C1 position, and modifies the double bond configuration (E/Z isomers) to optimize DNA binding affinity while maintaining dimer structure
Solution Approach 2:
The patent introduces specific local structural features including optional double bonds at defined positions and specific substituent patterns (R1-R9) at the C1 linkage point to enhance DNA binding while keeping other parts of the molecule flexible
2Reliability
If PBD dimers are linked through the C8 position, then DNA binding is improved, but the linkage creates structural constraints that limit versatility
Solution Approach 1:
The C1 linkage position serves multiple functions: it enables dimer formation, allows for E/Z isomerism, accommodates various substituent patterns, and maintains DNA binding capability, making it a universal linkage point for diverse PBD dimer architectures
Solution Approach 2:
The patent segments the molecule into distinct functional regions: the C1 linkage zone with optional double bonds, the substituent regions (R1-R9) for variability, and the core PBD structure for DNA interaction, allowing independent optimization of each segment
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compound effectively forms a stable bridge between PBD monomers, improving their DNA binding properties and potential as anti-proliferative agents by anchoring in the minor groove, avoiding DNA repair and interfering with DNA processing.
Implementation Method 1
a nucleophilic attack by the exocyclic C2-amino group of the central guanine occurs to form the covalent adduct
Implementation Method 2
form a covalent bond to a C2-amino group of guanine in DNA to form a DNA adduct
Implementation Method 3
locating at a low-energy binding sequence through Van der Waals, hydrogen bonding and electrostatic interactions
Implementation Method 4
Van der Waals, hydrogen bonding and electrostatic interactions
Implementation Method 5
Van der Waals, hydrogen bonding and electrostatic interactions
Data Source
AI summary
The invention relates to pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) of formula (I) and in particular to PBD dimers linked through the C1 position, and PBD monomers linked through the C1 position to aromatic groups, and pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents. (I) and salts or solvates thereof, wherein: the dotted lines indicates the optional presence of a double bond between C1 and C2 or C2 and C3; R2-R7 are independently selected substituent groups; and either: (i) R8 and R9 together form a double bond; (ii) R8 is H and R9 is OH; or (iii) R8 is H and R9 is ORA and RA is C1-6 alkyl; where R1 has the formula: -X-L-X′-D-X-L-X′- is a linker group and D has the formula (II) or (III): or where the compound is a dimer with each monomer being the same or different and being of formula (I) where the R1 of the first monomer and R′1 or R′6 of the second monomer, or R6 of the first monomer and R′1 of the second monomer, form together a bridge having the formula -X-L-X′- linking the monomers.