Traditional
chemotherapeutics used in cancer therapy do not preferentially
accumulate in tumor tissues. The conjugation to delivery vehicles
like antibodies or small molecules has been proposed as a strategy
to increase the tumor uptake and improve the therapeutic window of
these drugs. Here, we report the synthesis and the biological evaluation
of a novel small molecule–drug conjugate (SMDC) comprising
a high-affinity bidentate acetazolamide derivative, targeting carbonic
anhydrase IX (CAIX), and cryptophycin, a potent microtubule destabilizer.
The biological activity of the novel SMDC was evaluated in vitro,
measuring binding to the CAIX antigen by surface plasmon resonance
and cytotoxicity against SKRC-52 cells. In vivo studies showed a delayed
growth of tumors in nude mice bearing SKRC-52 renal cell carcinomas.
For biological applications, the control of the helix handedness of water‐soluble quinoline‐based oligoamide foldamers has been investigated by the installation of chiral end groups at either the C or N terminus. This has resulted in the development of monomer units capable of unequivocally inducing helical sense without impacting the aqueous solubility. Furthermore, we showed that very slow helix handedness inversion in water can be exploited. The incorporation of a chiral moiety with no handedness‐induction properties allows the chromatographic separation of P and M helices as diastereoisomers with kinetically locked handedness.
Phthalimide monofunctional hyperbranched polyglycerols (HbPG) were successfully synthesized, for the first time, by applying a new, highly efficient phthalimide/potassium phthalimide (PhthIm/K-PhthIm) initiating system for the anionic ring-opening multibranching polymerization of glycidol. As the analyses of the resulting polymers by UV and NMR spectroscopies, vapor pressure osmometry, aqueous and organic phase GPCs and ESI-MS proved, well-defined HbPGs with one phthalimide moiety, predetermined average molar masses, and narrow molar mass distributions were formed. The phthaloyl group was quantitatively cleaved by hydrazinolysis to form a monoamine functional HbPG. The amine functionality of the HbPG molecules at the initiating site was transformed into carboxylic, maleimide, and chloroacetamide groups. All functionalization reactions were quantitative as proved by multidimensional NMR spectroscopy. These findings indicate that the PhthIm/K-PhthIm combination can be utilized in the polymerization and subsequent derivatizations of other epoxides as well. In addition, the selectively modifiable reactive headgroup can be applied for obtaining various novel functionalized materials.
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