“…Langlois and co-workers have used the reductive cyclization approach for the synthesis of (+)-porothramycin and anthramycin analogues 84 and 85 (Scheme ) . They obtained the PBD ring system by selective reduction of the nitro aldehydes of type 83 with Raney-Ni catalyst.…”
Section: Cyclization Of Substituted N-benzoylpyrrolidine Precursorsmentioning
“…Langlois and co-workers have used the reductive cyclization approach for the synthesis of (+)-porothramycin and anthramycin analogues 84 and 85 (Scheme ) . They obtained the PBD ring system by selective reduction of the nitro aldehydes of type 83 with Raney-Ni catalyst.…”
Section: Cyclization Of Substituted N-benzoylpyrrolidine Precursorsmentioning
“…We prepared 4 according to the retrosynthetic route shown in Scheme , through reductive cyclization of the nitroaldehyde precursor A with Raney nickel, following the method developed in our laboratory. ,, The preparation of this nitroaldehyde involved as key steps a Horner−Wadsworth−Emmons reaction between a suitably functionalized phosphonate and the imide-vinylogous aldehyde B , itself derived from the enamide C , which could be prepared from ( S )-pyroglutaminol. 1 Structures of Anthramycin ( 1a ), Its Methyl Ether ( 1b ), Porothramycin B ( 2 ), and Its 9-Demethoxy Analogue ( 3 ) 1 …”
A new 7,8-methylenedioxy analogue (4) of (+)-porothramycin B (2) and its water-soluble sodium bisulfite derivative (15) have been synthesized in high yields and have been shown to exhibit high cytotoxic activities against several tumor cell lines. The new pyrrolo[2,1-c][1,4]benzodiazepine 4 was as effective against the resistant cell lines as against the doxorubicin-sensitive cell lines tested.
“…These properties differentiate PBDs from other families of DNA-alkylating agents, and both the chemical and biological aspects of these compounds have been explored by several research groups since the discovery of anthramycin in the 1960s. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Structure-activity relationship (SAR) information for the PBDs was initially established based on biological data obtained from natural compounds. [21][22][23] The development of an understanding of their mode of action prompted the rational design of synthetic analogues which provided additional chemical and biological information.…”
Section: Introductionmentioning
confidence: 99%
“…The PBDs have a right-handed twist due to the “ S ” - configuration at their C11a-position, which allows them to fit perfectly within the DNA minor groove. These properties differentiate PBDs from other families of DNA-alkylating agents, and both the chemical and biological aspects of these compounds have been explored by several research groups since the discovery of anthramycin in the 1960s. − …”
A comprehensive SAR investigation of the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomer antitumor agents is reported, establishing the molecular requirements for optimal in vitro cytotoxicity and DNA-binding affinity. Both carbocyclic and heterocyclic C2-aryl substituents have been studied ranging from single aryl rings to fused ring systems, and also styryl substituents, establishing across a library of 80 analogues that C2-aryl and styryl substituents significantly enhance both DNA-binding affinity and in vitro cytotoxicity, with a correlation between the two. The optimal C2-grouping for both DNA-binding affinity and cytotoxicity was found to be the C2-quinolinyl moiety which, according to molecular modeling, is due to the overall fit of the molecule in the DNA minor groove, and potential specific contacts with functional groups in the floor and walls of the groove. This analogue (14l) was shown to delay tumor growth in a HCT-116 (bowel) human tumor xenograft model.
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