A Multicomponent Protocol for the Synthesis of Highly Functionalized γ-Lactam Derivatives and Their Applications as Antiproliferative Agents

Abstract

An efficient synthetic methodology for the preparation of 3-amino 1,5-dihydro-2H-pyrrol-2-ones through a multicomponent reaction of amines, aldehydes, and pyruvate derivatives is reported. In addition, the densely substituted lactam substrates show in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell lines HEK293 (human embryonic kidney), MCF7 (human breast adenocarcinoma), HTB81 (human prostate carcinoma), HeLa (human epithelioid cervix carcinoma), RKO (human colon epithelial carcinoma), SKOV3 (human ovarian carcinoma), and A549 (carcinomic human alveolar basal epithelial cell). Given the possibilities in the diversity of the substituents that offer the multicomponent synthetic methodology, an extensive structure-activity profile is presented. In addition, both enantiomers of phosphonate-derived γ-lactam have been synthesized and isolated and a study of the cytotoxic activity of the racemic substrate vs. its two enantiomers is also presented. Cell morphology analysis and flow cytometry assays indicate that the main pathway by which our compounds induce cytotoxicity is based on the activation of the intracellular apoptotic mechanism.

Keywords: antiproliferative effect; multicomponent synthesis; γ-lactams.

Figure 1

Relevant γ-lactam-containing structures.

Scheme 1

Multicomponent synthesis of 1,5-dihydro-2H-pyrrol-2-ones 4–12.

Chart 1

1,5-dihydro-2H-pyrrol-2-ones 4–5 obtained (Ring numbering is shown for 4a).

Chart 2

1,5-Dihydro-2H-pyrrol-2-ones 6–12 obtained (Ring numbering is shown for 6a).

Scheme 2

Synthesis and hydrogenation of dimeric γ-lactam 16.

Chart 3

1,5-dihydro-2H-pyrrol-2-ones 18, 19 and derivatives 20 (Ring numbering is shown for 18a).

Scheme 3

Synthesis of γ-lactam derivative 21.

Figure 2

Antiproliferative activity of γ-lactam 4b.

Scheme 4

Synthesis and evaluation of each enantiomer of 4v.

Figure 3

Cell morphology visualization with X4 lens at 0, 6, 12, 24, and 48 h after exposure to compound 4b. Scale bar: 300 µm. (A) A549 cells treated with 1 µM of 4b. (B) A549 cells treated with 5 µM of 4b. (C) A549 cells were treated with 10 µM of 4b at 24 h. (D) A549 cells were treated with 15 µM of 4b at 24 h.

Figure 4

Percentages of early apoptotic (green bars), necrotic and late apoptotic (orange bars), and necrotic (red bars) A549 cells at 12, 24, and 48 h. after exposure to 4b.