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Review
. 2022 Jan 19;23(3):1075.
doi: 10.3390/ijms23031075.

From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues

Affiliations
Review

From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues

Oxana Kazakova et al. Int J Mol Sci. .

Abstract

This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.

Keywords: angiogenesis; antibiotic; ceragenine; claramine; diabetes; obesity; squalamine; triterpenoids; trodusquemine.

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Conflict of interest statement

The authors declare that they have no conflict of interest. All co-authors have seen and agreed with the contents of the manuscript and there is no financial interest to report.

Figures

Figure 1
Figure 1
The structures of squalamine 1, trodusquemine 2 and steroid polyamines 3–9.
Scheme 1
Scheme 1
Reagents and conditions: (a) 1. (COCl)2, CH2Cl2, 40 °C, 2 h; 2. (CH3)2CHCdBr, benzene, 25 °C, 1 h; 3. Ca(BH4)2, THF, 25 °C, 5 h; 4. TBDMsCl, imidazol, CH2Cl2, 16 °C, 16 h; 5. Cr(CO)6, t-BuOOH, CH3CN, 50 °C, 12 h; 6. Li, NH3, Et2O, −78 °C, 10 min; (b) 1. K-selectride, THF, −50 °C, 5 h; 2. NaCN, MeOH, 60 °C, 8 h; 3. (t-BuO)3Al, hexane, toluene, 110 °C, 20 h; (c) 1. C6H5CH2ONH2 HCl, Py, 115 °C, 16 h; 2. LiAlH4, Et2O, 35 °C, 16 h; (d) K2CO3, CH3CN, 50 °C, 20 h; (e) 1. C6H5CH2OCOCl, NaOH, THF, 0–25 °C, 4 h; 2. Na, NH3, THF, −78 °C, 18 h; 3. LiAlH4, Et2O, 35 °C, 6 h; 3. HCl, EtOH, 25 °C, 3 h; 4. SO3-Py, Py, 75 °C, 2 h.
Scheme 2
Scheme 2
Reagents and conditions: (a) 1. TsCl, Py, 14 h, 25 °C; 2. AcOK, MeOH, 4 h, 25 °C; 3. O3, MeOH, −78 °C; (b) 1. NaBH4, MeOH, 0–25 °C; 2. CH3SO2Cl, Et3N, CH2Cl2, 2 h, 0 °C; 3. NaI, acetone, 17 h, 25 °C; 4. PhSO2Na, DMF, 32 h, 25 °C; (c) 1. n-BuLi, 2 h, −78 °C; 2. Li, NH3, 30 min, −78 °C; 3. TsOH, dioxane/H2O, (7:3), 1 h, 80 °C; (d) 1. Ac2O, Py, 14 h, 25 °C; 2. CrO3, DMAP, CH2Cl2, 24 h, −20 °C; 3. Li, NH3, 10 min, −78 °C; 4. KB[CH(CH3)C2H5]3H, THF, 6 h, −50 °C; 5. Ac2O, DMAP, CH2Cl2, 14 h, 25 °C; (e) 1. CrO3, H2SO4, H2O, 7 h, 25 °C; 2. BocNH(CH2)4N(Boc)(CH2)3NH2, NaBH3CN, MeOH, 14 h, 25 °C; 3. HCl, MeOH, 11 h, 25 °C; 4. SO3-Py, Py, 6 h, 25 °C.
Scheme 3
Scheme 3
Reagents and conditions: (a) 1. Amberlist 15, acetone; 2. SO3-Py, Py, 6 h, 80 °C; (b) KOH, MeOH, 60 °C; (c) 1. NaBH4, CH(OCH3)3, MeOH, −78 °C; 2. Pt2O, CF3COOH, EtOH.
Scheme 4
Scheme 4
Reagents and conditions: (a) 4-chlorobutanol, H2O, 140–150 °C; (b) 1. Boc2O, EtOH, 48 h; 2. Et3N, MsCl, CH2Cl2, 16 h; (c) 1. NaN3, DMF, 48 h; 2. HCl, dioxane, 16 h; (d) 1. 31, NaOMe, MeOH, 24 h, −78 °C, NaBH4; 2. H2, Ni-Raney.
Scheme 5
Scheme 5
Reagents and conditions: (a) D. gossipina; (b) Li, NH3, THF; (c) TMSCl, OH(CH2)2OH; (d) NaOCl, TEMPO, NaBr, CH2Cl2; (e) P(O)CH2C(O)CH(CH3)2, Et2O, t-BuONa, THF; (f) 1. (R)-MeCBS, BH3 THF, toluene; 2. Et3N, toluene; 3. H2, Pt/C; (g) 1. p-TsOH, H2O, acetone; 2. SO3-Py, Py.
Scheme 6
Scheme 6
Reagents and conditions: (a) 1. CH3OCH2OCH3, P2O5, CHCl3, 25 °C; 2. OH(CH2)2OH, PTSA, benzene, 70 °C; 3. LiAlH4, THF, 25 °C; 4. (COCl)2, DMSO, Et3N, CH2Cl2, −78 °C, BuLi, Ph3PCH+(CH3)2I, THF; (b) (DHQD)2PHAL, K2OsO2(OH)4, K3Fe(CN)6, K2CO3, CH3SO2NH2, t-BuOH/t-BuOMe/H2O (2.5:3:2.5); (c) Ac2O, Py; (d) 1. CH3SO2Cl, DMAP, Et3N, CH2Cl2, 0–20 °C; 2. Pd/C, EtOAc, DMF, KOH, MeOH, 95 °C; (e) PPTS, t-BuOH; (f) BocNH(CH2)4NBoc(CH2)3NH2, NaBH3CN, 25 °C.
Scheme 7
Scheme 7
Reagents and conditions: (a) 1. Ac2O, Py, 110 °C, 4 h; 2. AD-mix-β, t-BuOH/H2O; 3. BzCl, Py, 0 °C, 24 h; (b) POCl3, Py, 25 °C, 12 h; (c) H2, 10% Pd-C, EtOAc, 25 °C, 4 h; (d) N-hydroxyphthalamide, EtOAc-acetone, C7H5O2, 25 °C, 4 h; (e) H2, PtO2, EtOAc, 25 °C, 3 h; (f) PCC, CH2Cl2, 25 °C, 12 h; (g) K2CO3, MeOH-CHCl3, 25 °C, 12 h; (h) K[CH(CH3)CH2CH3]3BH, THF, H2O2, −20 °C, 3 h; (i) Ag2CO3-ceolite, toluene, 25 °C, 8 h; (j) KOH, HO(CH2)2OH, 120 °C, 3 h; (k) SO3-Py, Py, 80 °C, 4 h; (l) NaOMe, H2N(CH2)3NH(CH2)4NH2 2HCl, NaBH3CN, H2, PtO2, 25 °C, 18 h.
Scheme 8
Scheme 8
Reagents and conditions: (a) TsCl, Py; (b) 1. KOAc, H2O, DMF; 2. Ac2O-Py; (c) PDC, TBHP, benzene; (d) 1. Pd/C, H2; 2. L-selectride, THF; (e) MOMCl, i-Pr2NEt, CH2Cl2; (f) LiAlH4, THF; (g) CrO3, Py, CH2Cl2.
Scheme 9
Scheme 9
Reagents and conditions: (a) LiAlH4, Et2O, 3Å, 12 h, 0–25 °C; (b) NaBH3CN, MeOH, 24 h, 25 °C; (c) CF3COOH, CHCl3, 25 °C; (d) SO3-Py, Py, 114 °C; (e) KOH, MeOH, 7 h, 60 °C.
Scheme 10
Scheme 10
Reagents and conditions: (a) PCC, CH2Cl2; (b) HO(CH2)2OH, TsOH, benzene; (c) 1. NaBH4, MeOH; 2. HCl, acetone; (d) 1. NaBH3CN, NH2(CH2)2NH2, NH2(CH2)4NH(CH2)3NH2, N,N-NH2(CH2)3NC2H4N(CH2)3NH2, THF, MeOH; 2. NaOH, THF.
Scheme 11
Scheme 11
Reagents and conditions: (a) trimethylsulfoxonium iodide, NaH, DMSO–THF, 2 h; (b) 1. NH2(CH2)2NHBoc, MeOH, 64 °C, 2 h; 2. 50% CF3COOH/CH2Cl2; 3. 50% DIPEA/CH2Cl2.
Scheme 12
Scheme 12
Reagents and conditions: (a) 1. HOBT/DCC/BOP/ methyl chloroformate, CHC12/THF/dioxane, −20 °C to 20 °C; 2. aluminum tri-tert-butoxide/aluminum triisopropoxide/Ag2CO3, benzene, toluene, cyclohexane, trifluorotoluene; (b) 1. RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; 2. NaBH4, MeOH, −78 °C, 2 h.
Scheme 13
Scheme 13
Reagents and conditions: (a) 1. OH(CH2)2OH, PTSA, benzene; 2. Imidazole, TBDMSCl, DMAP, CH2Cl2; (b) 1. RuCl3, TBHP, cyclohexane; 2. H2, 5% Pt/C, EtOAc; (c) K-selectride, THF; (d) 1N HCl, THF; (e) BnONH2 HCl, Py, EtOH; (f) LiAlH4, Et2O; (g) 1. NaBH(OAc)3, CH2Cl2; 2. 10% HCl, MeOH; 3. SO3-Py, MeOH.
Scheme 14
Scheme 14
Reagents and conditions: (a) NH2(CH2)4NBoc(CH2)3NHBoc, NaBH(OAc)3, THF; (b) NH2(CH2)3NBoc(CH2)4NBoc(CH2)3NHBoc, NaBH(OAc)3, THF; (c) SOCl2-MeOH, CH2Cl2.
Scheme 15
Scheme 15
Reagents and conditions: (a) RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; (b) NaBH4, MeOH, −78 °C, 2 h.
Scheme 16
Scheme 16
Reagents and conditions: (a) 1. RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; 2. NaBH4, MeOH, −78 °C, 2 h.
Scheme 17
Scheme 17
Reagents and conditions: (a) 1. Dihydropyran, TsOH, CH2Cl2, 1.5 h; 2. CrO3-Py, CH2Cl2; (b) 1. NH2(CH2)3NHBoc or NH2(CH2)4NHBoc, NaBH3CN, AcOH pH 5–6; 2. CF3COOH, CH2Cl2; (c) 1. Br(CH2)3CN, DMF, 60 °C; 2. LiAlH4, NiCl2 6H2O, THF; (d) 1. Amine, Ti(OiPr)4, MeOH, 20 °C, 5–6 h; 2. NaBH4, −78 °C, 2 h.
Scheme 18
Scheme 18
Reagents and conditions: (a) 1. (AcO)4Pb, (CH3)3SiN3, CH2Cl2; 2. LiAlH4, THF, 66 °C; (b) 1. CH2CHCN, MeOH; 2. LiAlH4,/NiCl2 6H2O, THF, 66 °C; 3. Br(CH2)3CN, DMF, 60 °C, 72 h; 4. LiAlH4,/NiCl2 6H2O, THF, 66 °C; (c) 1. AcOH, HNO3; 2. AcOH/Zn; 3. NH2OH HCl, Py.
Scheme 19
Scheme 19
Reagents and conditions: (a) 1. RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; 2. NaBH4, −78 °C, 2 h.
Scheme 20
Scheme 20
Reagents and conditions: (a) 1. HOCH2CH2OH, PTSA, benzene; TBSCl, imidazole, DMAP, CH2Cl2; 2. Li/NH3, THF; 3. LiAlH4, THF; (b) DAST, n-C5H12; 2. p-TsOH, acetone; (c) 1. NH2(CH2)4NBoc(CH2)3NHBoc, NaBH3CN, THF-MeOH; 2. SO3-Py, Py; 3. SOCl2, MeOH, CH2Cl2.
Scheme 21
Scheme 21
Reagents and conditions: (a) 1. NH2(CH2)4NH(CH2)3NH2, NH2(CH2)3NH(CH2)4NH(CH2)3NH2, DCC, Et3N, 7 h, 25 °C; 2. LiAlH4, THF, 6 h; 3. SO3-Py, Py, 5 h, 75 °C; 4. CF3COOH, CH2Cl2, 1 h, 25 °C.
Scheme 22
Scheme 22
Reagents and conditions: (a) 1. DCC, NH2(CH2)3NH(CH2)4NH(CH2)3NH2, NH2(CH2)4NH2, NH2(CH2)2NH(CH2)2NH(CH2)2NH(CH2)2NH2, CHCl3, 14 h, 25 °C; 2. SO3-Py, DMF.
Scheme 23
Scheme 23
Reagents and conditions: (a) bis(pentafluorophenyl)carbonate, 4-methylformalin, DMF, 1.5 h; (b) NH2(CH2)4NHBoc (n = 2, 4), NH2(CH2)3NBoc(CH2)4NBoc(CH2)3NHBoc, C8H19N, DMF, 2 days.
Scheme 24
Scheme 24
Reagents and conditions: (a) NH2(CH2)3NH(CH2)4NH(CH2)3NH2, DCC, BuOH, THF.
Figure 2
Figure 2
The structures of compounds 178–181.
Scheme 25
Scheme 25
Reagents and conditions: (a) RNH2, CH2Cl2, Et3N, 0 °C, 10 min/25 °C, 12 h.
Figure 3
Figure 3
The structures of compounds 184, 185.
Figure 4
Figure 4
The structure of ceragenins 186a and 186b [60,103].
Figure 5
Figure 5
The structure of squalamine phosphate 187.
Scheme 26
Scheme 26
Reagents and conditions: (a) NH2(CH2)3NH(CH2)3NH2, EEDQ, DMF, 60 °C, 4 h.
Scheme 27
Scheme 27
Reagents and conditions: (a) DSC, Et3N, CHCl3, acetonitrile, 50 °C, 3 h.
Scheme 28
Scheme 28
Reagents and conditions: (a) Succinimidyl ester of deoxycholic acid, CHCl3, r.t.
Scheme 29
Scheme 29
Reagents and conditions: (a) 1. Ac2O, Et3N, DMAP, CH2Cl2, 24 h; 2. NaBH3CN, AcOH, 48 h; 3. PCC, CaCO3, SiO2, CH2Cl2, 12 h; (b) 1. 1 eq. 4 DCE, AcOH, 1 eq diamine; 2. AcOH, NaBH(OAc)3, 4 days. (c) 1. 1 eq 4 in DCE, AcOH, 0.5 eq spermidine; 2. AcOH, NaBH(OAc)3, 4 days.
Figure 6
Figure 6
The structures of compounds 202, 203.
Figure 7
Figure 7
The structures of compounds 204206.
Scheme 30
Scheme 30
Reagents and conditions: (a) 1. p-TsCl/Py/CHCl3, 0 °C, 6 h; 2. HO(CH2)2OH, 1,4-dioxane, reflux, 4 h; 3. p-TsCl/Py/CHCl3, 0 °C, 6 h; (b) MeOH, toluene, reflux.
Scheme 31
Scheme 31
Reagents and conditions: (a) NaBH3CN, NH4OAc, MeOH; (b) 1. HCl, acetone; 2. NH2(CH2)3NH(CH2)4NH(CH2)3NH2, NaBH3CN, MeOH; (c) NaBH4, MeOH, 96%.
Scheme 32
Scheme 32
Reagents and conditions: (a) H2, Pd/C, MeOH, 90%; (b) NaBH3CN, NH4OAc, MeOH, 72%; (c) HCl, acetone, 68%; (d) NH(CH2)3NH(CH2)4NH(CH2)3NH2, NaBH3CN, 81%; € NaBH4, MeOH, 87%; (f) BnONH2 HCl, DMAP, Py, 90%; (g) SO3-Py, Py, 84%; (h) NH2(CH2)3NH(CH2)4NH2, NaBH3CN, LiOH, 76%.
Scheme 33
Scheme 33
Reagents and conditions: (a) 1. RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; 2. NaBH4, MeOH, −78 °C, 2 h.
Scheme 34
Scheme 34
Reagents and conditions: (a) 1. R1OH, PTSA, CH2Cl2, 60 °C, 8 h; 2. Al(OBu)3, acetone, toluene, 110 °C; 3. NH(CH2)3NH(CH2)4NH(CH2)3NH2, Ti(OiPr)4, MeOH, 20 °C, 24 h; 4. NaBH4, −78 °C.
Figure 8
Figure 8
The structures of compounds 223 and 224.
Figure 9
Figure 9
The structures of compounds 225 and 226.
Figure 10
Figure 10
The structures of ceragenins 186ac.
Scheme 35
Scheme 35
Reagents and conditions: (a) NC(CH2)3N(Boc)(CH2)3I 228, 95% HCOOH, LiAlH4, THF, 66 °C; (b) H2N(CH2)4N(Boc)(CH2)2CHO 230, benzene, Ti(OiPr)4, 80 °C; (c) NH2OH HCl, Py, 114 °C; (d) NaBH3CN, NH4OH, 15% TiCl3, MeOH, 25 °C; (e) H2N(CH2)3NH(CH2)4NH2, Ti(OiPr)4, 80 °C, benzene.
Scheme 36
Scheme 36
Reagents and conditions: (a) 1. CH2=CHCN, TEBAC, dioxane, 40% KOH, 25 °C, 26–36 h; 2. H2, Raney-Ni, MeOH, 100 °C, 100 atm, 19 h.
Scheme 37
Scheme 37
Reagents and conditions: (a) 1. (COCl)2, CHCl3, 2 h, 25 °C; 2. NH3 or NH2(CH2)6NH2, Et3N, CHCl3, 60 °C, 3 h; (b) CH2=CHCN, 40% KOH, dioxane, TEBAC, 14 h; (c) LiAlH4, THF; (d) NaBH4, i-PrOH, 0 °C, 2 h; (e) H2, Raney-Ni, MeOH, 100 °C, 100 atm, 8 h; (f) H2SO4, Ac2O, Py, 55 °C, 1 h, then 0 °C, 15 min.
Scheme 38
Scheme 38
Reagents and conditions: (a) CH2=CHCN, dioxane, 40% KOH, 25 °C, 2 h; (b) NH2OH HCl, NaHCO3, i-PrOH, 77 °C, 8 h; (c) NaBH4, BF3 Et2O, THF, 65 °C, 6 h; (d) H2, Raney-Ni, MeOH, 100 °C, 100 atm, 9 h.
Scheme 39
Scheme 39
Reagents and conditions: (a) R-NH2, Ti(OiPr)4 (1 eq.), MeOH, 20 °C, 12 h; NaBH4 (2 eq.), H2O, 0 °C, 2 h.
Scheme 40
Scheme 40
Reagents and conditions: (i) R-NH2, Ti(OiPr)4 (1 eq.), MeOH, 20 °C, 12 h; NaBH4 (2 eq.), −78 °C, 2 h.
Figure 11
Figure 11
The structures of triterpene conjugates with polyamines 267 [265,275], 268 [281], 269 [265], 270, 271 [300], 272, 273, 290 [298], 275, 299 [299], 276 [294,303], 277 [258], 278 [259], 279 [260], 280 [295,299], 281, 292 [302], 282 [289], 283 [274], 284 [304], 285 [287], 286 [291], 287 [284], 288 [277], 289 [285], 291 [283], 293 [296], 294 [280], 295 [297], 296 [279], 297 [274].
Figure 11
Figure 11
The structures of triterpene conjugates with polyamines 267 [265,275], 268 [281], 269 [265], 270, 271 [300], 272, 273, 290 [298], 275, 299 [299], 276 [294,303], 277 [258], 278 [259], 279 [260], 280 [295,299], 281, 292 [302], 282 [289], 283 [274], 284 [304], 285 [287], 286 [291], 287 [284], 288 [277], 289 [285], 291 [283], 293 [296], 294 [280], 295 [297], 296 [279], 297 [274].
Figure 12
Figure 12
Conjugates of oleanolic acid with spermine 300 and 301.
Figure 13
Figure 13
Conjugates of oleanolic acid with diethylenetriamine 302, triethylenetriamine 303, oleanonic acid conjugate with spermine spacered through propargylamide 304, and N-methyl-norspermidine 305.
Figure 14
Figure 14
Polyamine steroids exhibit diverse biological activity via several distinct mechanisms: permeabilization of bacterial and fungal membranes kills pathogens (A); modification of eukaryotic cell membranes renders them resistant to virions and misfolded proteins (B); inhibition of pathological angiogenesis hampers development of macular edema and tumors (C); PTP1B inhibition improves insulin sensitivity, decreases food intake and directly suppresses cancer cells proliferation (D).

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