Biosynthesis, asymmetric synthesis, and pharmacology, including cellular targets, of the pyrrole-2-aminoimidazole marine alkaloids

Abstract

The pyrrole-2-aminoimidazole (P-2-AI) alkaloids are a growing family of marine alkaloids, now numbering well over 150 members, with high topographical and biological information content. Their intriguing structural complexity, rich and compact stereochemical content, high N to C ratio (~1 : 2), and increasingly studied biological activities are attracting a growing number of researchers from numerous disciplines world-wide. This review surveys advances in this area with a focus on the structural diversity, biosynthetic hypotheses with increasing, but still rare, verifying experimental studies, asymmetric syntheses, and biological studies, including cellular target receptor isolation studies, of this stimulating and exciting alkaloid family.

Fig. 1

Common biosynthetic building blocks including dimethylallylpyrophosphate (3), acetyl and malonyl CoA (1,2), shikimic acid (4) leading to the steroid lanosterol (8), the polyketide brefeldin A (7), and the alkaloid podophylotoxin (9), respectively and the subject of this review, new building blocks, clathrodin and oroidin (5,6), leading to complex P-2-AIs including palau’amine (10).

Fig. 2

Dual reactivity of the common 2-aminoimidazole nucleus found in the P-2-AIs metabolites and numbering used in this review of the postulated precursor, clathrodin (5), containing the 2-aminoimidazole nucleus.

Fig. 3

Putative biosynthetic progression from simple amino acids to monomeric, dimeric, and tetrameric P-2-AIs, degradation products and possible shunt metabolites.

Fig. 4

(a) Structures of oroidin (6) and oroidin-inspired derivatives including ‘reverse amide’ derivatives displaying antibiofilm activity (b) Structure of the ageliferins and simplified derivatives demonstrating antibacterial activity

Fig. 5

Structures of P-2-AIs with antibacterial activity

Fig. 6

(a) Structure and pharmacology of girolline (73, a.k.a. giradazole) (b) key interactions between girolline and E site binding domain of 50 S ribosomal subunit (with permission from Elsevier-still needed)

Fig. 7

(a) Structure of 10Z-hymenialdisine (182) and summary of pharmacology (b) derivatization sites for kinase specificity studies (c) amine derivatives 184/185 used for affinity chromatography experiments

Fig. 8

P-2-AIs with anticancer potential but unknown cellular targets and summary of known SAR data

Fig. 9

Synthesis of a random (structure undefined) immunoaffinity fluorescence (IAF) tagged-sceptrin dervative 187 and its use in a sandwich assay using an IAF antibody (blue) to identify MreB (red) as an E. Coli binding protein of sceptrin.

Fig. 10

Structures of receptor antagonists, styillisadine A (188A) and dibromophakellin (20) and the immunosuppressive agent, palau’amine (10)

Fig. 11

Miscellaneous enzymatic inhibitory activities reported for several P-2-Ais including (a) phosphatase inhibitors, nagelamides A-C, G, and H (46A-C, G, H) (b) kinase inhibitors, konbu’acidin A (190) and spongiacidins A (189A) and B (189B), tauroacidins A (191A) and B (191B) and (c) a protein prenylation inhibitor, massadine (60).

Scheme 1

Possible routes to debromodispacamide B (11) and clathrodin (5) via (a) Pathway A: pyrrole oxidation and nucleophilic addition to an activated acyl pyrrole (b) Pathway B: dipeptide-based synthesis through diketopiperazines and intramolecular rearrangements

Scheme 2

Proposed biosyntheses of the P-2-AIs building blocks

Scheme 3

Büchi’s landmark ‘bioinspired’ synthesis of dibromophakellin (20) and more recent optimizations and isomerizations/rearrangements

Scheme 4

Proton-mediated isomerization of clathrodin/oroidin and further polycyclizations: alternative biosynthetic hypothesis for the formation of dibromophakellin and dibromoagelaspongin

Scheme 5

Intramolecular cyclizations of presumed precursors including tautomers and pre-transannular intermediates leading to bi-, tri-, and tetracyclic monomers

Scheme 6

‘ Ipso’ rearrangement of dibromophakellin (20) to cylindradine A (33)

Scheme 7

Proposed biogenesis of agelastatins and the related dimeric nagelamides

Scheme 8

Original Kinnel/Scheuer biosynthetic hypothesis for palau’amine involving a [4+2] cycloaddition/chorination/ring contraction sequence. (Inset: An isolated phakellin derivative supporting the proposed dehydrophakellin.)

Scheme 9

Tautomerism in the building blocks of the P-2-AIs

Scheme 10

Alternative “first-bond” dimerization pathways from clathrodine precursors

Scheme 11

Generation of molecular complexity in ‘higher order’ dimeric P-2-AIs from common multifaceted C7-C7′ precursors (intermediate B, 53)

Scheme 12

a) Proposed biosynthetic process for cyclopentane formation. b) Bioinspired approach by Harran mimicking this putative biosynthetic process.

Scheme 13

a) Proposed aziridinium intermediate suggested by an observed retention of configuration displacement of chloride by azide. b) Romo’s proposed biosynthesis of massadine based on this observation (ref. 37)

Scheme 14

Proposed biogenetic pathway for stylissazoles A-C (69A-C)

Scheme 15

Summary of biogenetic proposals for P-2-AIs dimers

Scheme 16

Enantioselective syntheses of girolline (73, a.k.a. giradazole). a) Commerçon’s aldol approach. b) Ahond’s chiral pool strategy. Tr = triphenylmethyl; Boc = t-butoxycarbonyl, Im = imidazole, DMF = N,N-dimethylformamide, THF = tetrahydrofuran.

Scheme 17

Concise, enantioselective synthesis of debromodispacamide D by Al Mourabit using a biomimetic oxidation. EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, DMAP = N,N-dimethylaminopyridine, m.s. = molecular sieves, DMF = N,N-dimethylformamide

Scheme 18

Enantioselective synthesis of cyclooroidin by Pelloux-Leon and Minassian. HOBT = N-hydroxybenzotriazole, DCC = dicyclohexylcarbodiimide, DMF = N-N-dimethylformamide, THF = tetrahydrofuran, NBS = N-bromosuccinimide. IBX = Iodoxybenzoic acid, TFA = trifluoroacetic acid

Scheme 19

Enantioselective syntheses of slagenins. a) Jiang’s synthesis of the antipodes of slagenins B and C. b) Gurjar’s synthesis of the natural enantiomers. BINAP = binaphthyl; TBS = t-butyldimethylsilyl; Im = imidazole, DMF = N,N-dimethylformamide, DMDO = dimethyldioxirane; THF = tetrahydrofuran; AIBN = azoisobutyronitrile. TBAF = tetrabutylammonium fluoride; Ts = p-toluenesulfonyl.

Scheme 20

Enantioselective syntheses of phakellin. a) Romo’s synthesis of (+)-phakellin b) Nagasawa’s synthesis of (+)-dibromophakellin. (IBX = iodoxobenzoic acid; DMSO = Dimethyl sulfoxide. DPPA = diphenylphosphoryl azide; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; THF = tetrahydrofuran, Tces = trichloroethylsulfonyl, HMDS = hexamethyldisilazane; TBS = t-butyldimethylsilyl; EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; DMAP = dimethylaminopyridine; Ms = Methanesulfonyl; py = pyridine; DIBAL = diisobutylaluminum hydride; Boc = t-butoxycarbonyl, Tf = trifluoromethylsulfonyl)

Scheme 21

Enantioselective syntheses of dibromophakellstatin. a) Romo’s synthesis of (+)- phakellstatin. b) Lindel’s synthesis of (−)-phakellstatin. KHMDS = potassium hexamethyldisilylazide, Bn = benzyl; DMDO = dimethyldioxirane; py=pyridine; Cbz = benzyloxycarbonyl; DMAP = dimethylaminopyridine, DIAD = diisopropylazodicarboxylate; TFA = trifluoroacetate; TBS = t-butyldimethylsilyl; DIBAL = diisobutylaluminum hydride, Ms = methanesulfonyl; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; THF = tetrahydrofuran; AIBN = azoisobutyronitrile; Ts = p-toluenesulfonyl.

Scheme 22

Summary of enantioselective syntheses of agelastatin. ^–

Scheme 23

Enantioselective synthesis of sceptrin (146) by Baran. PLE = pig liver esterase, DMT-MM = 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, TsOH = p-toluenesulfonic acid, DIBAL = diisobutylaluminum hydride, MsCl = methanesulfonyl chloride, DMF = N, N-dimethylformamide, THF = tetrahydrofuran.

Scheme 24

Conversion of sceptrin (146) to ageliferin (157) by Baran.

Scheme 25

Racemic synthesis of palau’amine by Baran. PMBCl = p-methoxybenzyl chloride, TBAI = tetrabutylammonium iodide, DMF = N, N-dimethylformamide, TMSOTf = trimethylsilyl trifluoromethanesulfonate, DIPEA = diisopropylethylamine, NBS = N-bromosuccinimide, THF = tetrahydrofuran, TFA = trifluoroacetic acid, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, IBX = 2-iodoxybenzoic acid, TFAA = trifluoroacetic anhydride, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, HOBt = N-hydroxybenzotriazole.

Scheme 26

Synthesis of all agelastatins isolated to date by Movassaghi; NBS = N-bromosuccinimide, THF = tetrahydrofuran, DTBMP = 2,6-di-tert-butyl-4-methylpyridine, CuTC = copper (I) thiophene-2- carboxylate. (* = overall yields calculated from reported step-wise yields)