Reduction of Progranulin-Induced Breast Cancer Stem Cell Propagation by Sortilin-Targeting Cyclotriazadisulfonamide (CADA) Compounds.

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.

Syntheses and anti-HIV and human cluster of differentiation 4 (CD4) down-modulating potencies of pyridine-fused cyclotriazadisulfonamide (CADA) compounds.

CADA compounds selectively down-modulate human cell-surface CD4 protein and are of interest as HIV entry inhibitors and as drugs for asthma, rheumatoid arthritis, diabetes and some cancers. Postulating that fusing a pyridine ring bearing hydrophobic substituents into the macrocyclic scaffold of CADA compounds may lead to potent compounds with improved properties, 17 macrocycles were synthesized, 14 with 12-membered rings having an isobutylene head group, two arenesulfonyl side arms, and fused pyridine rings bearing a para substituent. The analogs display a wide range of CD4 down-modulating and anti-HIV potencies, including some with greater potency than CADA, proving that a highly basic nitrogen atom in the 12-membered ring is not required for potency and that hydrophobic substituents enhance potency of pyridine-fused CADA compounds. Cytotoxicities of the new compounds compared favorably with those of CADA, showing that incorporation of a pyridine ring into the macrocyclic scaffold can produce selective compounds for potently down-modulating proteins of medicinal interest.