Bimodal Use of Chiral α-Trifluoromethylalanine in Aib Foldamers: Study of the Position Impact Towards the Helical Screw-Sense Preference.

Oligomers of the achiral α-aminoisobutyric acid (Aib) adopt a 3 helical conformation in which the screw-sense preference can be controlled by a single chiral residue. The use of the fluorinated residue α-Trifluoromethylalanine (α-TfmAla) revealed a unique way to both induce and measure the screw-sense preference of such oligomers acting as F NMR probe. This work proposes a systematic study of the effect of this fluorinated chiral inducer on the helical screw-sense preference of poly-Aib oligomers.

Optimizing the enzymatic release of MMAE from DGR-based small molecule drug conjugate by incorporation of a GPLG-PABC enzymatically cleavable linker.

Antibody-Drug Conjugates (ADCs) and Small Molecule-Drug Conjugates (SMDCs) represent successful examples of targeted drug-delivery technologies for overcoming unwanted side effects of conventional chemotherapy in cancer treatment. In both strategies, a cytotoxic payload is connected to the tumor homing moiety through a linker that releases the drug inside or in proximity of the tumor cell, and that represents a key component for the final therapeutic effect of the conjugate. Here, we show that the replacement of the Val-Ala--aminobenzyloxycarbamate linker with the Gly-Pro-Leu-Gly--aminobenzyloxycarbamate (GPLG-PABC) sequence as enzymatically cleavable linker in the SMDC bearing the [DKPDGR] αβ integrin ligand as tumor homing moiety and the monomethyl auristatin E (MMAE) as cytotoxic payload led to a 4-fold more potent anti-tumoral effect of the final conjugate on different cancer cell lines.

Introducing the Chiral Constrained α-Trifluoromethylalanine in Aib Foldamers to Control, Quantify and Assign the Helical Screw-Sense.

Oligomers of α-aminoisobutyric acid (Aib) are achiral peptides that adopt 3 helical structures with equal population of left- and right-handed conformers. The screw-sense preference of the helical chain may be controlled by a single chiral residue located at one terminus. H and F NMR, X-ray crystallography and circular dichroism studies on new Aib oligomers show that the incorporation of a chiral quaternary α-trifluoromethylalanine at their N-terminus induces a reversal of the screw-sense preference of the 3 -helix compared to that of a non-fluorinated analogue having an l-α-methyl valine residue.

Conjugates of Cryptophycin and RGD or DGR Peptidomimetics for Targeted Drug Delivery.

RGD-cryptophycin and DGR-cryptophycin conjugates were synthetized by combining peptidomimetic integrin ligands and cryptophycin, a highly potent tubulin-binding antimitotic agent across lysosomally cleavable Val-Ala or uncleavable linkers. The conjugates were able to effectively inhibit binding of biotinylated vitronectin to integrin αβ, showing a binding affinity in the same range as that of the free ligands. The antiproliferative activity of the novel conjugates was evaluated on human melanoma cells M21 and M21-L with different expression levels of integrin αβ, showing nanomolar potency of all four compounds against both cell lines.

Synthesis and Biological Evaluation of RGD and isoDGR-Monomethyl Auristatin Conjugates Targeting Integrin α β.

This work reports the synthesis of a series of small-molecule-drug conjugates containing the α β -integrin ligand cyclo[DKP-RGD] or cyclo[DKP-isoDGR], a lysosomally cleavable Val-Ala (VA) linker or an "uncleavable" version devoid of this sequence, and monomethyl auristatin E (MMAE) or F (MMAF) as the cytotoxic agent. The conjugates were obtained via a straightforward synthetic scheme taking advantage of a copper-catalyzed azide-alkyne cycloaddition as the key step. The conjugates were tested for their binding affinity for the isolated α β receptor and were shown to retain nanomolar IC values, in the same range as those of the free ligands.

Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting.

RGD-α-amanitin and isoDGR-α-amanitin conjugates were synthesized by joining integrin ligands to α-amanitin via various linkers and spacers. The conjugates were evaluated for their ability to inhibit biotinylated vitronectin binding to the purified αβ receptor, retaining good binding affinity, in the same nanomolar range as the free ligands. The antiproliferative activity of the conjugates was evaluated in three cell lines possessing different levels of αβ integrin expression: human glioblastoma U87 (αβ+), human lung carcinoma A549 (αβ-) and breast adenocarcinoma MDA-MB-468 (αβ-).

Synthesis, antileishmanial activity and cytotoxicity of 2,3-diaryl- and 2,3,8-trisubstituted imidazo[1,2-a]pyrazines.

A series of original 2-phenyl-3-(pyridin-4-yl)imidazo[1,2-a]pyrazines and the 3-iodo precursors, bearing a polar moiety at the C-8 position, was synthesized and evaluated for their antileishmanial activities. Two derivatives exhibited very good activity against the promastigote and the amastigote forms of Leishmania major in the micromolar to submicromolar ranges, coupled with a low cytotoxicity against macrophages and 3T3 mouse fibroblast cells. Through LmCK1 inhibition assay, investigations of the putative molecular target of these promising antileishmanial compounds will be discussed.

Synthesis and antiproliferative activity of benzofuran-based analogs of cercosporamide against non-small cell lung cancer cell lines.

A novel series of 3-methyl-1-benzofuran derivatives were synthesized and screened in vitro for their antiproliferative activity against two human NSCLC cell lines (NSCLC-N6 mutant p53 and A549 wild type p53). Most promising compounds presented a structural analogy with the west part of cercosporamide, a natural product of biological interest. In particular, compounds 10, 12 and 31 showed cytotoxic activities at micromolar concentrations (IC₅₀ < 9.