Investigation of the Lactam Side Chain Length Necessary for Optimal Indenoisoquinoline Topoisomerase I Inhibition and Cytotoxicity in Human Cancer Cell Cultures

Abstract

Indenoisoquinolines with lactam substituents such as ethylamino, propylamino, and butylamino have previously demonstrated potent biological activity, but optimal length has never been established. In the present study, a series of simplified indenoisoquinoline analogues possessing a linker spacing of 0-12 carbon atoms between the lactam nitrogen and the terminal amino group have been prepared, determining that 2-4 atom lengths are optimal for topoisomerase I inhibition and cytotoxicity. Using these lengths, analogues were prepared with the amino group and portions of the linker replaced by a pyridine ring. A three-carbon spacer within the pyridine series still demonstrated potent topoisomerase I inhibition.

Investigation of the Structure–Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase I Poisons

“…21 The selection of a three-carbon polymethylene linker between the lactam nitrogen and the side chain nitrogen in the final products is consistent with prior studies indicating that the optimal length is 2–4 atoms in comparable systems. 35 …”

Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: Investigating the hypothesis of shared structure–activity relationships

“…Indenoisoquinolines substituted with di- and polyamines are potent top1 inhibitors 31–32. It is known in general that di- and polyamine conjugates are effective “DNA-targeting” moieties for many classes of intercalating and anti-top1 compounds 31–35.…”

“…It is known in general that di- and polyamine conjugates are effective “DNA-targeting” moieties for many classes of intercalating and anti-top1 compounds 31–35. In 2007, Morrell et al determined that diamines with two- to four-carbon spacers were optimal substituents for bioactivity when placed on indenoisoquinolines 31. The question as to whether this SAR trend could also be applied to aromathecins served as a rationale for the synthesis of 14-[(aminoalkyl)-aminomethyl)aromathecins 53–63 .…”

Synthesis and biological evaluation of dialkylaminoalkylamino benzo[c][1,7] and [1,8]phenanthrolines as antiproliferative agents

“…In a continuation of our work, we report here the synthesis and biological activities of new series of 1,7-BZP and 1,8-BZP bearing at positions C2 and C1 on cycle A, respectively, different dialkylaminoalkyl substituents. These side chains, which mimick natural DNA ligands such as spermine and spermidine, were chosen due to the excellent results reported with such substituents in several related series including indén-oisoquinoléines [9], dibenzo[c,h] [1,6]naphthyridinones [10], camptothécine [11], and acronycine analogs [12].…”

“…(s, 1H),9.03 (d, 1H, J ¼ 5.5 Hz),8.53 (d, 1H, J ¼ 5.5 Hz), 8.52 (d, 1H, J ¼ 9.2 Hz), 8.36 (d, 1H, J ¼ 9.2 Hz), 7.88 (s, 1H), 7.43 (s, 1H)). MS (ESþ) m/z 325/327 [M þ H] þ .…”