Mild, efficient conditions have been developed for the preparation
of 4-methylbenzhydrylamine
polystyrene (MBHA) and aminomethyl polystyrene (AMPS) resins by a
two-step procedure with
synthons 1a and 1c. The products possess
excellent swelling characteristics and acylate readily
with linkers yielding useful derivatives, which retain good swelling
and reactivity. Comparative
studies with these resins, and their poly(ethylene glycol) (PEG)
derivatives, yield insights into the
role of spacer arm and environment effects in synthesis
facilitation.
The results of this study show that classic olefination chemistry can be adapted to a solid-phase format for parallel synthesis of analog libraries. Although yields varied for the individual analogs, sufficient quantity of pure material was obtained directly from the resin for structural characterization and biological evaluation. This study further validates solid-phase organic synthesis as a useful approach for rapid parallel-manifold library synthesis to augment both lead compound discovery and optimization.
Antibody-drug conjugates (ADCs) represent an important class of emerging cancer therapeutics. Recent ADC development efforts highlighted the use of pyrrolobenzodiazepine (PBD) dimer payload for the treatment of several cancers. We identified the isoquinolidinobenzodiazepine (IQB) payload (D211), a new class of PBD dimer family of DNA damaging payloads. We have successfully synthesized all three IQB stereoisomers, experimentally showed that the purified (,)-D211 isomer is functionally more active than (,)-D221 and (,)-D231 isomers by >50,000-fold and ∼200-fold, respectively. We also synthesized a linker-payload (D212) that uses (,)-D211 payload with a cathepsin cleavable linker, a hydrophilic PEG8 spacer, and a thiol reactive maleimide. In addition, homogeneous ADCs generated using D212 linker-payload exhibited ideal physicochemical properties, and anti-CD33 ADC displayed a robust target-specific potency on AML cell lines. These results demonstrate that D212 linker-payload described here can be utilized for developing novel ADC therapeutics for targeted cancer therapy.
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