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Macrocyclic triamine disulfonamides can be synthesized by double Tsuji–Trost N-allylation reaction of open-chain disulfonamides with 2-alkylidene-1,3-propanediyl bis(carbonates). The previously used Atkins–Richman macrocyclization method generally gives lower yields and requires more tedious purification of the product. Solvent, palladium source, ligand, and concentration have all been varied to optimize the yields of two key 12-membered ring bioactive compounds, CADA and VGD020. The new approach tolerates a wide range of functional groups and gives highest yields for symmetrical compounds in which the acidities of the two sulfonamide groups are matched, although the yields of unsymmetrical compounds are still generally good. The method has also been extended to the synthesis of 11-membered rings, pyridine-fused macrocycles, and products bearing an ester or aryl substituent on the exocyclic double bond.

Cyclotriazadisulfonamide (CADA) compounds selectively down-modulate two human proteins of potential therapeutic interest, cluster of differentiation 4 (CD4) and sortilin. Progranulin is secreted from some breast cancer cells, causing dedifferentiation of receiving cancer cells and cancer stem cell proliferation. Inhibition of progranulin binding to sortilin, its main receptor, can block progranulin-induced metastatic breast cancer using a triple-negative in vivo xenograft model. In the current study, seven CADA compounds (CADA, VGD020, VGD071, TL020, TL023, LAL014, and DJ010) were examined for reduction of cellular sortilin expression and progranulin-induced breast cancer stem cell propagation. In addition, inhibition of progranulin-induced mammosphere formation was examined and found to be most significant for TL020, TL023, VGD071, and LAL014. Full experimental details are given for the synthesis and characterization of the four new compounds (TL020, TL023, VGD071, and DJ010). Comparison of solubilities, potencies, and cytotoxicities identified VGD071 as a promising candidate for future studies using mouse breast cancer models.

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