ABSTRACT
A high-valent, rhenium(V) oxo complex (PCP)ReOCl2 (1; PCP=bis(2,6-di-tert-butylphosphinomethyl)phenyl) undergoes a deprotonation and "dearomatization" upon treatment with LiN(SiMe3 )2 to give (P*CP)ReOCl (2 a), in which Re is bound to a new dianionic P*CP ligand. Compound 2 a was studied spectroscopically, structurally, and computationally and was determined to have non-negligible Re=C multiple bond character, leading to its formulation as a new pseudo-carbenoid species. Reaction of 2 a or its iodo analogue (P*CP)ReOI (2 b) with CO2 provided access to (PCP)ReOX(CO2 ) (X=Cl or I, 3 a/b), the product of 1,3-cycloaddition and C-C bond formation.
ABSTRACT
Camptothecin (CPT) is a promising anticancer drug, yet its therapeutic potential has been limited by poor water solubility and facile hydrolysis of the lactone form into an inactive carboxylate form at neutral pH. In this work, a fundamental synthetic methodology was advanced to allow for the preparation of well-defined functional polyphosphoramidate (PPA)-based block copolymers that coassembled with CPT into nanoparticles, which underwent coincident acid-triggered polymer backbone degradation, nanoparticle disassembly, and CPT release. Encapsulation of CPT by the PPA polymer inhibited premature hydrolysis of CPT at pH 7.4 and enabled accelerated CPT release at pH 5.0 (ca. 4× faster than at pH 7.4). Two degradable oxazaphospholidine monomers, with one carrying an alkyne group, were synthesized to access well-defined block PPAs (dispersity, D<1.2) via sequential organobase-catalyzed ring-opening polymerizations (ROP). The resulting amphiphilic block copolymers (PEOMP-b-PBYOMP) were physically loaded with CPT to achieve well-dispersed nanotherapeutics, which allowed the aqueous suspension of CPT at concentrations up to 3.2 mg/mL, significantly exceeding the aqueous solubility of the drug (<2.0 µg/mL at 37 °C). Cytotoxicity studies revealed enhanced efficacy of the CPT-loaded nanoparticles over free CPT in cancer cells and similar toxicity in normal cells.
