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We have developed combinatorial libraries of new 1,3-imidazoline-2-thiones 5 and 2-phenylimino-1,3-thiazolines 7 by way of different reaction sequences of the same three components, gamma-chloroacetoacetanilides 1, amines 2, and isothiocyanates 3 in a parallel synthetic fashion. One of the building blocks, the gamma-chloroacetoacetanilides 1, was prepared by the sequential reaction of 4-methylene-oxetan-2-one (ketene dimer) with chlorine and various anilines. The condensation of 1 with amines gave dihydrofuran 4 intermediates that when reacted with 3 afforded the 1,3-imidazoline-2-thiones 5. On the other hand, reaction of 3 with 2 provided substituted thioureas 6 that were reacted with 1 to yield 2-phenylimino-1,3-thiazolines 7.

Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. Our findings highlight the potential of SL-145 in suppressing metastatic TNBC independent of the HSR.