Herein we report the synthesis and biological activity evaluation of 2,4 linked azole-containing molecules.

The first total synthesis of marthiapeptide A is reported. Two synthetic procedures are described: the first, which was unsuccessful, attempts to close the ring at position I, and the second, which was successful, closes the ring at position II. It appears that the first route was unsuccessful because it required cyclization next to the rigid thiazole moiety, whereas the second route closed next to the more flexible thiazoline ring.

The established cytotoxic agent RITA contains a thiophene-furan-thiophene backbone and two terminal alcohol groups. Herein we investigate the effect of using thiazoles as the backbone in RITA-like molecules and modifying the terminal groups of these trithiazoles, thereby generating 41 unique structures. Incorporating side chains with varied steric bulk allowed us to investigate how size and a stereocenter impacted biological activity. Subjecting compounds to growth inhibition assays on HCT-116 cells showed that the most potent compounds ,, and had GI values of 4.4, 4.4, and 3.4 μM, respectively, versus RITA (GI of 800 nM). Analysis of these compounds in apoptosis assays proved that ,, and were as effective as RITA at inducing apoptosis. Evaluating the impact of on proteins targeted by RITA (p53, c-Myc, and Mcl-1) indicated that it acts via a different mechanism of action to that of RITA. RITA suppressed Mcl-1 protein via p53, whereas compound suppressed Mcl-1 expression via an alternative mechanism independent of p53.

Herein, we developed a bifunctional reagent rac-2-Br-DMNPA 2 for the late-stage protection of peptide cysteine. Through the identification of its t-Bu ester 1 as a more competent form under ligation conditions, facile N-terminal and side-chain caging for the model peptide and protein were accomplished. Building upon this, a one-pot ligation and photolysis strategy was applied in the synthesis of the mini-protein chlorotoxin. More importantly, we extended the utility of 2 as a bifunctional linker for traceless solid-phase chemical ligation.