Design, Synthesis, and Antiproliferative Activity of Novel Neocryptolepine-Rhodanine Hybrids

Abstract

A series of novel neocryptolepine-rhodanine hybrids (9a,b, 11a-d, 14, and 16a,b) have been synthesized by combining neocryptolepine core 5 modified at the C-11 position with rhodanine condensed with the appropriate aryl/hetero aryl aldehydes. Based on these findings, the structures of the hybrids were confirmed by spectral analyses. By employing the MTT assay, all hybrids were tested for their in vitro antiproliferative activity against two cancer cell lines, including MDA-MB-231 (human breast) and HepG-2 (hepatocellular carcinoma). Interestingly, the IC₅₀ values of all hybrids except 9b and 11c showed activity comparable to the standard anticancer drug, 5-fluorouracil, against HepG-2 cancer cells. Furthermore, the cytotoxicity of all the synthesized hybrids was investigated on a normal skin human cell line (BJ-1), and the results showed that these compounds had no significant cytotoxicity toward these healthy cells at the highest concentration used in this study. This study also indicated that the active hybrids exert their cytotoxic activity via the induction of apoptosis. A molecular docking study was used to shed light on the molecular mechanism of their anticancer activity. The docking results revealed that the hybrids exert their mode of action through DNA intercalation. Furthermore, in silico assessment for pharmacokinetic properties was performed on the most potent compounds, which revealed candidates with good bioavailability, high tolerability with cell membranes, and positive drug-likeness values.

Keywords: alkaloids; docking; hybrids; neocryptolepine; pharmacokinetics; rhodanine.

Figure 1

Indoloquinoline from CryptolePis Sanguinolenta.

Figure 2

Some biological applications of rhodanine structures C.

Scheme 1

Synthesis of neocryptolepine 5. Reagents and conditions: (a) N-chlorosuccinimide, 1,4-dimethylPiperazine, CH₂Cl₂, 0 °C, 2 h. b. Trichloroacetic acid, room temperature, 2 h. (b) Diphenyl ether, reflux, 3 h. (c) POCl₃, toluene, reflux, 12 h.

Scheme 2

A plausible mechanism for the formation of product 3.

Scheme 3

Formation and mechanism of cyclic ketone 4.

Scheme 4

A possible method for the manufacture of compound 5.

Scheme 5

Synthesis of 11-aminoalkylene aminoneocryptolepine 7a,b. Reagents and conditions: (d) Excess alkylene bisamine 6a,b, neat, reflux 5–10 min.

Scheme 6

Proposed mechanism of aromatic nucleophilic substitution for the synthesis of 7a,b.

Scheme 7

Reagents and conditions: Pathway A: (e) ethyl bromoacetate 8, CS₂, acetonitrile r.t, 12–24 h. (f) NaOAc, glacial acetic acid, stirring, reflux 6–8 h. Pathway B: (g) ethyl chloroacetate 12 (1 mmol), r.t 30 min–1 h, CS₂ (2 mmol) in (2 mL) DMF, KOH (3 mmol) and 10 a,b (1 mmol), r.t overnight.

Scheme 8

Mechanism of rhodanine ring formation 9a,b. R = alkylene amino neocryptolepine.

Scheme 9

Plausible mechsm of hybrids 11a–d formation via Knoevenagel condensation reaction with aldehydes 10a,b. where R = alkylene amino neocryptolepine, Ar = Ph or 4-hydroxyphenyl.

Scheme 10

Synthesis of neocryptolepine–rhodanine hybrids 16a,b. Reagents and conditions: (h) DMF, Et₃N, reflux 1–4 h.(f) Sodium acetate, glacial acetic acid, stirring with reflux, 12–24 h.

Figure 3

(A): Index number of acridine displayed in molecular interactions. (B) Representation of the molecular interactions of the 1t8i crystal structure, where blue dashed lines refer to hydrogen bond interactions, green dashed lines display electrostatic interactions and red lines show steric interactions.

Figure 3

(A): Index number of acridine displayed in molecular interactions. (B) Representation of the molecular interactions of the 1t8i crystal structure, where blue dashed lines refer to hydrogen bond interactions, green dashed lines display electrostatic interactions and red lines show steric interactions.

Figure 4

Ribbon diagram of 1t8i crystal structure; the highlighted part demonstrates acridine connected to a single DNA strand.