RGD Peptidomimetic MMAE-Conjugate Addressing Integrin αVß3-Expressing Cells with High Targeting Index.

Small molecule-drug conjugates (SMDCs) mimicking the RGD sequence (-Arg-Gly-Asp-) with a non-peptide moiety require a pharmacophore-independent attachment site. A library of 36 sulfonamide-modified RGD mimetics with nM to pM affinity for integrin αV ß3 was synthesized and analysed via DAD mapping. The best structure of the conjugable RGD mimetic was used and a linker was attached to an aromatic ring by Negishi cross-coupling. The product retained high affinity and selectivity for integrin αV ß3 . The conjugable RGD mimetic was then attached to an enzymatically cleavable GKGEVA linker equipped with a self-immolative PABC and the antimitotic drug monomethyl auristatin E (MMAE). The resulting SMDC preferred binding to integrin αV ß3 over α5 ß1 in a ratio of 1 : 4519 (ELISA) and showed selectivity for αV ß3 -positive WM115 cells over αV ß3 -negative M21-L cells in the in vitro cell adhesion assay as well as in cell viability assays with a targeting index of 134 (M21-L/WM115).

Stereoselective synthesis of enantiomerically pure bowl-shaped hydroxytribenzotriquinacenes.

Enzyme-catalysed hydrolysis of the inherently chiral aryl acetate rac-11 bearing the bowl-shaped tribenzotriquinacene (TBTQ) core enables the stereoselective synthesis of the enantiomerically pure (M)-2-hydroxytribenzotriquinacene (M)-12. Starting from rac-11, for which two independent routes are described, the use of immobilised lipase CAL-A in buffered biphasic solution at pH 7 led to the TBTQ-phenol (M)-12 in 33% yield and with >99% ee on a preparative scale. Extended enzyme screening revealed that the use of CAL-B gives the same enantioselectivity. Furthermore, the chiroptical properties of the enantiomerically pure TBTQ-acetates (M)-11 and (P)-11, TBTQ-phenols (M)-12 and (P)-12 and the corresponding 2-hydroxy-3-iodotribenzotriquinacenes (M)-13 and (P)-13 are reported.