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

Abstract

The aromathecin topoisomerase I (top1) inhibitors offer promising scaffolds for the development of novel cancer chemotherapeutics. They are 'composites' of the camptothecin and indenoisoquinoline top1 inhibitors. Interestingly, some structure-activity relationship (SAR) overlap between the aromathecins and the indenoisoquinolines has been observed. For both classes, placement of certain polar groups in similar regions of the heteroaromatic system improves top1 inhibitory and antiproliferative activities. A series of water-soluble aromathecins substituted at position 14 with diaminoalkanes of various lengths has been prepared. These compounds all possess similar antiproliferative potency, but a general trend is observed: aromathecins with longer diaminoalkane substituents (>6 carbons) possess lower anti-top1 activity than their smaller counterparts (2-4 carbons), presumably as a result of unfavorable hydrophobic interactions. This trend is also noted with the indenoisoquinolines, revealing additional SAR overlap that supports the hypothesis that there is a 'universal' top1 inhibitor SAR.

Figure 1

Representative Top1 Inhibitors.

Figure 2

Top1-mediated DNA cleavage induced by aromathecins 53, 55, 57, 58, 60, and 63. Lane 1: DNA alone; lane 2: Top1 alone; lane 3: 1, 1 µM; lane 4: 6, 1 µM; lane 5: 8, 100 µM; lanes 6–29: 53, 55, 57, 58, 60, and 63 at 0.1, 1, 10, and 100 µM, respectively, from left to right. Numbers and arrows on right indicate arbitrary cleavage site positions.

Figure 3

Hypothetical model of aromathecin 53 in ternary complex with top1 and DNA showing proposed hydrogen bonds. Water molecules are red spheres; distances are between heavy atoms. The stereoview is programmed for wall-eyed viewing.

Figure 4

Hypothetical model of water-mediated hydrogen bonds and polar contacts between diaminoethyl side chain of aromathecin 53, Asn352, and DNA base pairs. Water molecules are indicated in red, other structures are colored by atom type. Distances are between heavy atoms.

Figure 5

Ligand overlay of hypothetical ternary complex models of aromathecin 53 (green) and indenoisoquinoline 64 (cyan). The positions of the lactam nitrogen and 14-position are also shown in their respective colors.

Figure 6

Structure of Indenoisoquinoline 64.

Scheme 1

Reagents and Conditions: (a) i. cat. 2-cyclohexen-1-one, cyclohexanol, reflux, ii. maleic acid, EtOAc, r.t.; (b) FeCl₃, SOCl₂, reflux; (c) MeOH, Et₃N, r.t.; (d) i. DMSO, (COCl)₂, CH₂Cl₂, −78 °C, ii. Et₃N, −78 °C–r.t.; (e) reflux.

Scheme 2

Reagents and Conditions: (a) i. BCl₃·Me₂S, 1,2,-dichloroethane, 0 °C, ii. chloroacetonitrile, AlCl₃, reflux. iii. 2 M HCl, reflux; (b) p-TsOH, toluene, reflux.

Scheme 3

Reagents and Conditions: (a) Boc₂O, CHCl₃, r.t.; (b) DMSO, r.t.; (c) 3 M HCl, MeOH, CHCl₃, r.t. or 3 M HCl, MeOH, benzene, reflux (47).