Camptothecin (CPT) selectively traps topoisomerase 1-DNA cleavable complexes (Top1cc) to promote anticancer activity. Here, we report the design and synthesis of a new class of neutral porphyrin derivative 5,10-bis(4-carboxyphenyl)-15, 20-bis(4-dimethylaminophenyl)porphyrin (compound 8) as a potent catalytic inhibitor of human Top1. In contrast to CPT, compound 8 reversibly binds with the free enzyme and inhibits the formation of Top1cc and promotes reversal of the preformed Top1cc with CPT. Compound 8 induced inhibition of Top1cc formation in live cells was substantiated by fluorescence recovery after photobleaching (FRAP) assays. We established that MCF7 cells treated with compound 8 trigger proteasome-mediated Top1 degradation, accumulate higher levels of reactive oxygen species (ROS), PARP1 cleavage, oxidative DNA fragmentation, and stimulate apoptotic cell death without stabilizing apoptotic Top1-DNA cleavage complexes. Finally, compound 8 shows anticancer activity by targeting cellular Top1 and preventing the enzyme from directly participating in the apoptotic process.

Expedient synthesis, spectroscopic, solid state structural proof, and theoretical study of helically twisted weakly aromatic hybrid singly Nconfused ferrocenoporphyrinoids and the peripheral coordinated Rh(I) complex are reported. The X-ray crystal structure of the macrocycles reveals an ambiguously inverted pyrrole ring reinforcing regioselective β,β-linkage with the spatially adjacent N-confused N-methyl pyrrole ring leading to endocyclic extension of macrocyclic π-conjugation via tricyclic [5.5.5] moiety. The three-dimensional structure with built-in fused tricyclic [5.5.5] moiety has paved way to three-dimensional weak diatropicity with vis−NIR absorptions. The peripheral coordinated Rh(I) complex owing to helical chirality about the macrocyclic ring and planar chirality about the square planar Rh coordination site exists as a mixture of diastereomers (5:3) with well resolved 1 H NMR spectra anticipating weak aromaticity. The experimental spectroscopic measurements are in agreement with theoretically determined electronic structure and properties strongly elucidating sustained weak diatropic ring currents in twisted macrocycles both in neutral form and in the metalated complex. Further fragment molecular orbital approach and molecular orbital theory gave insights on the stability of N-confused β−β fused oxoferrocenoporphyrinoids and formation of the selective peripheral coordinated Rh(I) complex.

High-yield synthesis, spectroscopic and solid-state structural proof of the lactam-embedded smallest ever metal-free stable Huckel antiaromatic trans-doubly N-confused [16] porphyrins are reported. These new facets of trans-doubly Nconfused porphyrins have been anticipated to exhibit the redox-associated variation of Huckel aromaticity as a mere consequence of the amido-like structures of the Nconfused N-methyl pyrrole rings of the macrocycles. Strong aromaticity upon NaBH 4 reduction leading to a resonance dipolar structure of the [18]π-conjugated system as the reduced congener with concomitant Huckel topology are the important highlights. Excellent agreement between experimental spectroscopic measurements and the theoretically determined properties elucidate aromaticity switching upon chemical reduction. Recent years have witnessed an upsurge of demand for the experimental realization of stable antiaromatic systems because of their versatile applications in material science. The conformational rigidity and the enriched stability of these novel 16π antiaromatic doubly N-confused porphyrins might entitle these macrocycles toward such applications.

A water-soluble meso-carboxy aryl substituted [18] heteroannulene (porphyrin) and its Zn-complex have been found to be viable in targeting α-Syn aggregation at all its key microevents, namely, primary nucleation, fibril elongation, and secondary nucleation, by converting the highly heterogeneous and cytotoxic aggresome into a homogeneous population of minimally toxic off-pathway oligomers, that remained unexplored until recently. With the EC 50 and dissociation constants in the low micromolar range, these heteroannulenes induce a switch in the secondary structure of toxic prefibrillar on-pathway oligomers of α-Syn, converting them into minimally toxic nonseeding off-pathway oligomers. The inhibition of the aggregation and the reduction of toxicity have been studied in vitro as well as inside neuroblastoma cells.

meso-Aryl substituted highly stable single conformers of doubly mutant porphodimethenes.