Marine-Derived Natural Lead Compound Disulfide-Linked Dimer Psammaplin A: Biological Activity and Structural Modification

Abstract

Marine natural products are considered to be valuable resources that are furnished with diverse chemical structures and various bioactivities. To date, there are seven compounds derived from marine natural products which have been approved as therapeutic drugs by the U.S. Food and Drug Administration. Numerous bromotyrosine derivatives have been isolated as a type of marine natural products. Among them, psammaplin A, including the oxime groups and carbon-sulfur bonds, was the first identified symmetrical bromotyrosine-derived disulfide dimer. It has been found to have a broad bioactive spectrum, especially in terms of antimicrobial and antiproliferative activities. The highest potential indole-derived psammaplin A derivative, UVI5008, is used as an epigenetic modulator with multiple enzyme inhibitory activities. Inspired by these reasons, psammaplin A has gradually become a research focus for pharmacologists and chemists. To the best of our knowledge, there is no systematic review about the biological activity and structural modification of psammaplin A. In this review, the pharmacological effects, total synthesis, and synthesized derivatives of psammaplin A are summarized.

Keywords: biological activity; marine natural product; psammaplin A; structural modification.

Figure 1

The chemical structure of psammaplin compounds, biprasin and UVI5008.

Scheme 1

Synthesis route of psammaplin A by the Lindel group. Reagents and conditions: (a) LDA, THF, −78 °C, 15 h; (b) NEt₃·3HF, MeOH, rt, 30 min; (c) (i) H₂, Pd/C, dioxane, rt, 41 h; (ii) LiOH·H₂O, THF/H₂O, rt, 40 h; (d) cystamine dihydrochloride, NHS, DCC, Et₃N, DMF, rt, 15 h.

Scheme 2

Synthesis route of psammaplin A of the Harburn Group. Reagents and conditions: (a) Rhodanine, NH₄OAc, toluene, reflux; or Rhodanine, NaOAc, AcOH, reflux; (b) (i) NaOH, H₂O; (ii) HCl (10%), 0 °C; (iii) HCl·NH₂OBn, NaOAc, EtOH, 70 °C; (c) cystamine dihydrochloride, EDC, HOBt, Et₃N, CH₂Cl₂; (d) TMSI, CH₂Cl₂.

Scheme 3

Synthesis route of psammaplin A of the Park group. Reagents and conditions: (a) ethyl acetoacetate, piperidine, AcOH; (b) H₂, Pd/C, MeOH; (c) KBrO₃, KBr, 0.5 M-HCl, MeOH; (d) n-BuONO, AcOEt, NaOEt, EtOH, 0 °C; (e) DHP, PTSA, CH₂Cl₂; (f) 1 N-KOH, EtOH; (g) N-hydroxyphthalimide, EDC, 1,4-dioxane; (h) (i) cystamine, Et₃N, MeOH, 1,4-dioxane; (ii) 1 N HCl/Et₂O CH₂Cl₂/MeOH.

Figure 2

Schematic representation of the antimicrobial activity of psammaplin A.

Figure 3

Schematic representation of the cytotoxic effects of psammaplin A.

Figure 4

Chemical structures of the synthetic homodimeric derivatives 18‒21.

Figure 5

Chemical structures of three types of psammaplin A derivatives 22‒28.

Figure 6

Chemical structures of the representative heterodimeric derivatives 29‒33.

Scheme 4

Synthesis of psammaplin A bis-triazole derivatives 40 and 41. Reagents and conditions: (a) BBr₃/CH₂Cl₂, 0 °C, rt, 4 h; (b) NaN₃/DMF, 5 h, 90 °C; (c) K₂CO₃, 18-crown-6, 2-dimethylaminoethyl chloride or 3-chloro-N,N-dimethylpropan-1-amine, acetone, reflux; (d) CuSO₄/sodium ascorbate, DMF/H₂O (2:1), 24 h, rt.

Scheme 5

Synthesis of psammaplin A analogues 46, 47, 53, and 54. Reagents and conditions: (a) NaOAc, N-Ac-Gly, Ac₂O; (b) HCl; (c) HONH₂·HCl, pyridine; (d) EDCI, N-hydroxy-succinamide dioxane; nucleophile, NEt₃, dioxane/MeOH; HCl, CH₂Cl₂/Et₂O/MeOH; (e) Pd(OAc)₂, P(o-Tol)₃, NEt₃, DMF; (f) osmium(VIII) oxide, NMO, MeCN/water; (g) NBS, DMF; (h) p-TsOH·H₂O, benzene; HONH₂·HCl, NaOAc, MeOH; (i) cystamine, AlMe₃, CH₂Cl₂.

Figure 7

Chemical structures of the psammaplin A derivatives 55‒77.

Figure 8

Chemical structures of the psammaplin A derivatives 78‒89.

Scheme 6

Synthesis of indole-based psammaplin A derivative 96. Reagents and conditions: (a) K₂CO₃, CH₂Cl₂, 25 °C, 20 h; (b) K₂CO₃, CH₂Cl₂, TrCl, 25 °C, 20 h; (c) LiOH·H₂O, THF/H₂O (1:1), 25 °C, 20 h; (d) cystamine, EDC, NHS, dioxane, 25 °C, 2 h; (e) 1 M HCl in Et₂O, CH₂Cl₂, 25 °C, 2 h.

Figure 9

Chemical structures of the psammaplin A fluorescent derivatives 97‒100.

Scheme 7

Synthesis of photopsammaplin 111. Reagents and conditions: (a) propane-1,3-diol, p-TsOH, toluene, rt, 2.5 h; (b) Mg, THF, rt, 2 h; then 0 °C, 2,2,2-trifluoro-1-(piperidin-1-yl)ethanone, 2 h, rt; (c) (i) HONH₂·HCl, pyridine, rt, 9 h; (ii) NEt₃, p-TsCl, 24 h, 0 °C to rt; (d) NH₃, 6 h, −78 °C to rt; (e) NEt₃, I₂, 15 min, 0 °C, then 3 h, rt, avoiding daylight; (f) 0.5 M H₂SO₄, acetone/H₂O, rt, 12 h, quant; (g) LDA, THF, −78 °C, 14 h; (h) (i) NEt₃·3HF, MeOH, rt, 2 h; (ii) HONH₂·HCl, MeOH, rt, 17 h, quant; (i) LiOH·H₂O, THF/H₂O, rt, 20 h, quant; (j) cystamine dihydrochloride, NHS, DCC, NEt₃, DMF, rt, 15 d.

Scheme 8

Synthesis of psammaplin A analogue 119. Reagents and conditions: (a) CF₃SO₃H; (b) amine, heating neat or microwave neat; (c) hν, R₂-SH; (d) air.

Figure 10

Chemical structures of the psammaplin A derivatives 120‒124.

Scheme 9

Synthesis of psammaplin A analogues 133 and 134. Reagents and conditions: (a) hydantoin, ethanolamine, EtOH, H₂O, reflux, 5 h; (b) NaOH, H₂O, reflux, 12 h; (c) NH₂OH·HCl, NaOH, NaHCO₃, H₂O, rt, overnight; (d) cystamine dihydrochloride, EDCI, HOBt, THF, rt, 24 h.