Comparative Evaluation of the Antibacterial and Antitumor Activities of Marine Alkaloid 3,10-Dibromofascaplysin

Abstract

Fascaplysins form a group of marine natural products with unique cationic five-ring coplanar backbone. Native fascaplysin exhibits a broad spectrum of bioactivities, among which the cytotoxic activity has been the most investigated. Several fascaplysin derivatives have more selective biological effects and are promising as lead compounds. Thus, the introduction of a substituent at C-9 of fascaplysin leads to a strong increase in its antimicrobial properties. Here, a comparative assessment of the antimicrobial activity of synthetic analogs of the marine alkaloids 3-bromofascaplysin, 10-bromofascaplysin, and 3,10-dibromofascaplysin, along with some of their isomers and analogs, was carried out against a panel of Gram-positive bacteria in vitro. For the first time, a significant increase in the antimicrobial activity of fascaplysin was observed when a substituent was introduced at C-3. The introduction of two bromine atoms at C-2 and C-9 enhances the antimicrobial properties by 4 to 16 times, depending on the tested strain. Evaluation of the antimicrobial potential in vivo showed that fascaplysin and 3,10-dibromofascaplysin had comparable efficacy in the mouse staphylococcal sepsis model. Additionally, 3,10-dibromofascaplysin demonstrated a strong and reliable antitumor effect in vivo on the Ehrlich carcinoma inoculated subcutaneously, with a value of tumor growth inhibition by 49.2% 20 days after treatment. However, further studies on alternative chemical modifications of fascaplysin are needed to improve its chemotherapeutic properties.

Keywords: 3,10-dibromofascaplysin; antibacterial activity; antitumor efficacy; fascaplysin derivatives.

Figure 1

Structures of 12H-pyrido[1,2-a:3,4-b′]diindole (1) and fascaplysins 2–5.

Figure 2

The structures of fascaplysin derivatives 6–9 with high antibacterial activity.

Scheme 1

Preparation of 3-bromofasaplysin (3) and 2,10-dibromofascaplysin (13). Reagents and conditions: (a) I₂ (0.8 equiv.), DMSO, 110 °C, 4 h; (b) 220 °C, 40 min, and HCl (aq).

Scheme 2

Synthesis of 3,10-dibromofascaplysin (5) and its isomer 14. Reagents and conditions: (a) 4-bromobutanal (16, 4.0 equiv.), EtOH, H₂O, autoclave, 150 °C, 1 h; (b) 2,4-dibromoacetophenone (11a) (1 equiv.), I₂ (0.8 equiv.), DMSO, 110 °C, 1 h, then tryptamines 10b, 17 (1.0 equiv.), DMSO, 110 °C, 4 h; (c) 220 °C, 15 min, then HCl (aq).

Scheme 3

Synthesis of a series of disubstituted fascaplysin derivatives 21–24. Reagents and conditions: (a) NBS (2.0 equiv.), AcOH, 90 °C, 1 h; (b) Cl₂ (excess), AcOH, r.t., 2 h; (c) Cl₂ (excess), AcOH, 60 °C, 1 h; (d) 200 °C, 1–2 h, then HCl (aq).

Figure 3

Survival curves (Kaplan–Meier) of mice infected with S. aureus after intravenous (i.v.) administration of 3,10-dibromofascaplysin (A) and vancomycin (B). Mice (n = 10 for each group) were treated 1 h after infection via corresponding single doses of the drugs shown on the curves.

Figure 4

Dynamics of tumor growth. Change in tumor volume (A) and tumor growth index (B) by day 20 in different groups of animals. Vehicle—control group of animals (untreated); DOX—group of animals treated with doxorubicin at a dose of 0.25 mg/kg; 5—3,10-dibromofascaplysin at a dose of 7.56 mg/kg. Results are presented as mean ± SEM (n = 10). The significance of the differences was estimated via one-way ANOVA, followed by Tukey’s test versus the saline group. Significant differences are presented as * p < 0.05, ** p < 0.01, and *** p < 0.001.