Total Synthesis and Antiproliferative Activity Screening of (±)-Aplicyanins A, B and E and Related Analogues

Abstract

The first total synthesis of the indole alkaloids ()-aplicyanins A, B and E, plus seventeen analogs, all in racemic form is reported. Modifications to the parent compound included changing the number of bromine substituents on the indole, the groups on the indole nitrogen (H, Me or OMe), and/or the oxidation level of the heterocyclic core tetrahydropyrimidine. Each compound was screened against three human tumor cell lines, and fourteen of the newly synthesized compounds showed considerable cytotoxicity. The assay results were used to establish structure-activity relationships.These results suggest that the acetyl group moiety on the imine nitrogen, and the bromine at position 5 of the indole, are both critical to activity.

Halogenated Indole Alkaloids from Marine Invertebrates

“…They also exhibit antimitotic activity [38]. Lastly, given the high cytotoxicity typical of bromoindole derivatives, the presence of a bromoindole moiety in some aplicyanins warrants their investigation as anticancer drugs.…”

“…Lastly, given the high cytotoxicity typical of bromoindole derivatives, the presence of a bromoindole moiety in some aplicyanins warrants their investigation as anticancer drugs. Recently, the first total synthesis of (±)-aplicyanins A, B, and E and 17 analogues has been reported [38]. …”

“…In order to establish the structure-activity relationships of the aplicyanins, the total synthesis of (±)-aplicyanins A, B, and E, plus 17 analogues was carried out by Sísa and co-workers in 2009 [38]. The compounds were again screened for cytotoxicity against the same three human tumor cell lines used for the natural compounds.…”

Synthesis, Biological Evaluation and Molecular Docking of Novel Indole-Aminoquinazoline Hybrids for Anticancer Properties

“…The indole nucleus, on the other hand, is prevalent in many heterocycles with antimicrobial, antioxidant, anticancer and anti-tubercular activities [4,5,6,7]. A lipophilic bromine atom on the fused benzo ring of an indole framework has been found to impart significant anti-tumour activity in both synthetic [8] and naturally [9] occurring indoles, such as aplicyanin A (Figure 1B), shown in Figure 1. The latter exhibits increased antiproliferative activity against the human breast cancer (MDA-MB-231), lung cancer (A549) and colon cancer (HT-29) cell lines [9].…”

“…A lipophilic bromine atom on the fused benzo ring of an indole framework has been found to impart significant anti-tumour activity in both synthetic [8] and naturally [9] occurring indoles, such as aplicyanin A (Figure 1B), shown in Figure 1. The latter exhibits increased antiproliferative activity against the human breast cancer (MDA-MB-231), lung cancer (A549) and colon cancer (HT-29) cell lines [9]. 4-(1-Benzyl-1 H -indol-3-yl)-6,7-dimethoxyquinazoline (Figure 1C) is an example of an indole-quinazoline hybrid that was previously found to exhibit moderate ErbB-2 activity, with little or no activity against the epidermal growth factor receptor [10].…”