Synthesis and Biological Activities of Azalamellarins

Abstract

The synthesis of azalamellarins, a new series of lactam analogues of biologically active lamellarins, was achieved using Cu(I)-mediated and microwave-assisted C-N(amide) bond formation. Seventeen azalamellarins, including N-allylazalamellarins and N-propylazalamellarins chi-D, L-N, and J-dehydro J, were synthesized and evaluated for their cytotoxicity against the cancer cell lines HuCCA-1, A-549, HepG2, and MOLT-3. The results showed that certain azalamellarins exhibited good activities in the micromolar IC(50) value range (IC(50)=the drug concentration that causes 50 % of cell-growth inhibition after 72 h of continuous exposure to the test molecule), comparable to their parent lamellarin analogue.

Facile and Divergent Synthesis of Lamellarins and Lactam‐Containing Derivatives with Improved Drug Likeness and Biological Activities

“…From pyrrole amide 17 or 18 , intramolecular C−N bond formation was then performed by using copper(I) thiophene‐2‐carboxylate (CuTC) under MW‐assisted conditions to generate the lactam ring, as previously reported, except that Cs 2 CO 3 was also added and the reaction time was extended to 45 min to drive the reaction to completion (Scheme ). The resulting N,O‐protected dihydroazalamellarin D ( 21 or 22 ) then underwent DDQ oxidation smoothly to install the C5=C6 olefin.…”

“…In the presence of thioanisole, the N ‐benzyl group still remained unaffected under various conditions (Table , entries 3 and 4), whereas the N ‐PMB group was successfully removed to furnish azalamellarin D in 79–85 % yield (Table , entries 6 and 7) . As described in the Experimental Section, all the optimized conditions were then employed to synthesize azalamellarin N, of which only the N‐protected forms were obtained as the final products in the previous study …”

“…The crude product was purified by column chromatography (20–30 % EtOAc/hexane) to give a 1.5:1 mixture of 11 / 13 as a brown sticky product (3.76 g) along with the starting material (3.87 g). The spectroscopic data are in agreement with those previously reported …”

Synthesis of Phenanthridinone Derivatives by Direct Arylation. Characterization of the Absorption and Emission Spectra for Representative Examples

“…60 Uma reação tipo Goldberg catalisada por um sal de cobre utilizando derivados de ácido 2-clorobifenil-2'-carboxílico com anilinas forneceu 1a (72%) e 1r (96%). 77 Métodos radicalares incluem: o uso de t-BuOK (Figura 2, C) fornecendo 1q (bromo substrato, 61-70%, iodo substrato, 63%), 38 deidrogenação de N-fenil bifenil-2-carboxamida (Figura 2, D) utilizando persulfato de potássio para obter 1r (97%), 78 ou por geração fotolítica de um íon N-acilnitrênio gerando 1r (65%), 79 ou por foto-deidro-halogenação (Figura 2, C) fornecendo 1r (25%). C podemos confirmar as principais modificações nos grupos, como por exemplo a ausência da ligação C-I (~90 ppm), que pode indicar a ciclização ou somente a redução da ligação C-I.…”

Progress on lamellarins

“…7 Robust synthesis of Lam-D has enabled SAR and mechanism of action studies. Thus, the vast chemical space of the Lam structure has been explored through modified 30 analogs, including 1-dearyl, 8 2-dearyl, 9 lactone-free derivatives, 10 lactam, 11 and polymeric and peptidic nuclear location signal conjugates. 12,13 Herein, in addition to the recent synthetic strategies developed for total synthesis of Lam-D and its numerous 35 naturally occurring and synthetic analogs, recent work on SAR studies and on using multi-target mechanisms to induce apoptosis are also discussed.…”