ABSTRACT
A procedure for the selective synthesis of 3,4-diaryl-1H-pyrazoles through a 1,3-dipolar cycloaddition is reported. The transformation occurred under mild conditions using affordable tosylhydrazones and nitroalkenes commencing from benzaldehydes/heteroaromatic aldehydes as starting materials. Due to the versatility of this protocol, we prepared a vast collection of 3,4-diaryl-1H-pyrazoles, which included the incorporation of heterocyclic rings at the pyrazole core. Two-dimensional NMR techniques (2D-NOESY and HMBC) confirmed the regioselectivity of the transformation and correlated well with DFT calculations. Accordingly, the analysis of the transition states indicated that the 3,4-diaryl product corresponded to the product with the lowest activation energy and led to the most stable product. Finally, the series was evaluated against three cancer cell lines, with compound 8f being the most remarkable analog in terms of activity and extraordinary selectivity towards PC-3 compared to the other cell lines (including COS-7).
ABSTRACT
We report a practical two-step approach involving a Ugi 4-CR/ azide-alkyne cycloaddition for the synthesis of biaryl-containing cyclophanes. The series represents an extension of our previously reported macrocycles as an effort to enhance the anti-proliferative activity of this scaffold. In this variant, we incorporate a biphenyl moiety in the framework, thus enhancing the macrocycle size, lipophilicity, and structural diversity. Macrocycles were tested against different cell lines, being more cytotoxic against prostate (PC-3 and DU-145) and breast (MCF-7) tumor cells. Gratifyingly, the most active compound showed a significative enhancement of PC-3 growth inhibition with respect to our previous series, reaffirming the potential anti-proliferative activity of this kind of cyclophanes.
