To
replace dimethylformamide (DMF) in fluorenylmethoxycarbonyl
(Fmoc) solid-phase peptide synthesis, we explored the application
of mixtures of green solvents (green solvents mixtures for solid-phase
peptide synthesis (GM-SPPS)) as combinations of Cyrene (dihydrolevoglucosenone),
sulfolane, or anisole with dimethyl carbonate or diethyl carbonate,
in different proportions. Their ability to swell differently functionalized
polystyrene and polyethylene glycol resins was explored, and solubility
of amino acids and coupling reagents was studied. Moreover, the synthesis
of the model peptide Aib-enkephalin was performed in the new green
mixtures, confirming the possibility to fully replace DMF all over
SPPS. The two established best green protocols were then successfully
applied to the synthesis of a longer peptide (Aib-ACP). Finally, the
green solvent-based procedure was applied to the synthesis of the
reduced form of the active pharmaceutical ingredient (API) Octreotide.
After oxidative cyclization and a single high-pressure column chromatography,
the pharmaceutical-grade compound was isolated in comparable high
yield to that obtained with the standard procedures.
A novel class of dehydro-β-proline-containing peptidomimetics, designed to be effective as α4β1 integrin ligands, has been developed on the basis of the fundamental requirements for the interactions of these transmembrane receptors with bioactive ligands. Dehydro-β-proline ring has been synthesized through an original pathway, involving ring closing metathesis of a diallylamino derivative. The synthesized products showed to be effective and selective as α4β1 integrin antagonists and displayed IC50 values in the nanomolar range in cell adhesion inhibition assays and in VCAM-1-induced phosphorylation of extracellular-signal-regulated kinases. Significant activity was observed also toward the homologous integrin α4β7, while they did not display any activity toward selected members of β1, β2, and β3 families. A strong dependence on the stereochemistry of the heterocyclic central core could be observed. The great importance of α4β1 integrin in chronic inflammatory and autoimmune diseases suggests a possible exploitation of these ligands as lead compounds for therapeutic tools development.
A significant improvement in the treatment of trypanosomiases has been achieved with the recent development of nifurtimox-eflornithine combination therapy (NECT). As an alternative to drug combinations and as a means to overcome most of the antitrypanosomatid drug discovery challenges, a multitarget drug design strategy has been envisaged. To begin testing this hypothesis, we designed and developed a series of quinone-coumarin hybrids against glyceraldehyde-3-phosphate dehydrogenase/trypanothione reductase (GAPDH/TR). These enzymes belong to metabolic pathways that are vital to Trypanosoma brucei and Trypanosoma cruzi, and have thus been considered promising drug targets. The synthesized molecules were characterized for their dual-target antitrypanosomal profile, both in enzyme assays and in in vitro parasite cultures. The merged derivative 2-{[3-(3-dimethylaminopropoxy)-2-oxo-2H-chromen-7-yl]oxy}anthracene-1,4-dione (10) showed an IC50 value of 5.4 μM against TbGAPDH and a concomitant Ki value of 2.32 μM against TcTR. Notably, 2-{4-[6-(2-dimethylaminoethoxy)-2-oxo-2H-chromen-3-yl]phenoxy}anthracene-1,4-dione (compound 6) displayed a remarkable EC50 value for T.brucei parasites (0.026 μM) combined with a very low cytotoxicity toward mammalian L6 cells (7.95 μM). This promising low toxicity of compound 6 might be at least partially due to the fact that it does not interfere with human glutathione reductase.
The replacement of
toxic solvents with greener alternatives in
Heck–Cassar–Sonogashira (HCS) cross-couplings was investigated.
The fine-tuning of the HCS protocol allowed to achieve complete conversions
and high speed under mild conditions.
N
-Hydroxyethylpyrrolidone
(HEP) gave the best results. Moreover, the methodology was successfully
applied to the synthesis of an intermediate of the anticancer drug
Erlotinib, demonstrating the versatility of the new green protocol.
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