Thiopeptide antibiotics: retrospective and recent advances

Abstract

Thiopeptides, or thiazolyl peptides, are a relatively new family of antibiotics that already counts with more than one hundred different entities. Although they are mainly isolated from soil bacteria, during the last decade, new members have been isolated from marine samples. Far from being limited to their innate antibacterial activity, thiopeptides have been found to possess a wide range of biological properties, including anticancer, antiplasmodial, immunosuppressive, etc. In spite of their ribosomal origin, these highly posttranslationally processed peptides have posed a fascinating synthetic challenge, prompting the development of various methodologies and strategies. Regardless of their limited solubility, intensive investigations are bringing thiopeptide derivatives closer to the clinic, where they are likely to show their veritable therapeutic potential.

Figure 1

Members of new classes of antibiotics. Abu = aminobutyric acid.

Figure 2

Classification of thiopeptide antibiotics into different series. Their characteristic central six-member ring is highlighted in bold.

Figure 3

Some of the most recently described thiopeptides.

Figure 4

The biosynthetic gene cluster of tiomuracins and their precursor peptide sequence, which is coded in the structural gene. In the precursor peptide sequence, the structural peptide is numbered with positive figures and the leading peptide with negative ones. Residues that appear in the mature thiopeptide are underlined.

Scheme 1

Biosynthetic pathway of thiomuracin I. LP = leading peptide. Enzymes involved in the biosynthetic pathway (TdpX) are named according to their corresponding gene (tdpX) in thiomuracins’ gene cluster (tdp).

Scheme 2

Biosynthesis of indolic acid moietiy from Trp and incorporation into nosiheptide. Enzymes involved in the biosynthetic pathway (NosX) are named according to their corresponding gene (nosX) in gene cluster of nosiheptide (nos).

Scheme 3

Biosynthesis of quinaldic acid moietiy from Trp and incorporation into thiostrepton.

Scheme 4

Proposed mechanisms for C-terminal amide formation during nosiheptide and thiostrepton maturation.

Figure 5

Thiopeptides have macrocycles of different sizes that determine their mode of action.

Figure 6

Thiopeptides with tipA promoting activity. A very preserved region, which has been shown to interact with the ribosome/L11 complex, is highlighted (solid squares). Radamycin, devoid of antibacterial activity, has a mutated sequence in the previously mentioned region (hashed squares). Promothiocin B possesses the same mutated residues, but maintains antibacterial activity, though in a 26-membered macrocycle.

Figure 7

29-membered thiopeptides with a very preserved Asn residue highlighted with a square.

Figure 8

Cyclothiazomycin and its more recently isolated analogs B1 and B2.

Figure 9

Proximity induced covalent capture. Mutated L11 protein has an external Cys residue in the area where interaction with the tail of thiostrepton is expected. Tsr = thiostrepton.

Scheme 5

Kelly’s synthesis of dimethyl sulfomycinamate. Reagents and conditions: (a) Br₂, pyridine, rt, 77%; (b) MeI, K₂CO₃, acetone, reflux, overnight 88%; (c) KMnO₄, 90 °C, 3 h; (d) ClCO₂Me, Et₃N, DMAP, CH₂Cl₂, 0 °C to rt, 2 h, 65%; (e) AlCl₃, CH₂Cl₂, reflux, 2 days, 93%; (f) Tf₂O, 2,6-lutidine, CH₂Cl₂, 0 °C, 5 min, 95%; (g) 5, PdCl₂(PPh₃)₂, 1,4-dioxane, 100 °C, overnight 97%; (h) NBS, THF, H₂O, rt, 10 min, 95%; (i) 6, THF sealed tube, 100 °C, 3 days, 65%; (j) OsO₄, NaIO₄, 1,4-dioxane, H₂O, rt 3 h, 85%; (k) 7, Sn₂Bu₆, PdCl₂(PPh₃)₂, Pd(PPh₃)₄, LiCl, 1,4-dioxane, 100 °C, overnight, 35%.

Scheme 6

Shin’s synthesis of GE2270A central core. Reagents and conditions: (a) H₂S, DMAP, Et₃N, pyridine, rt, 3 days, 90%; (b) i. KHCO₃, BrCH₂COCO₂Et, THF, 0 °C, then rt, overnight; ii. TFAA, pyridine, THF, 0 °C, 1 h, then rt, overnight, 53%; (c) Tf₂O, DMAP, pyridine, 0 °C, 1 h, then rt, overnight, 93%; (d) ethyl vinyl ether, Et₃N, dppp, Pd(OAc)₂, toluene, reflux, overnight, 73%; (e) NBS, THF, H₂O, rt, 5 min; (f) i. 10, KHCO₃, DME, 0 °C, 1 h, then rt, overnight; ii. TFAA, pyridine, 0 °C, 2 h, 63% (2 steps); (g) 2 M HCl in THF, rt, 24 h; (h) i. 12, Et₃N, toluene, rt, 15 min; ii. MnO₂, toluene, rt, 12 h, 41% (2 steps). dppp = 1,3-bis(diphenylphosphino)propane; Pac = Phenacyl.

Scheme 7

The synthesis of ent-GE2270A central core by Bach. Reagents and conditions: (a) BuLi, ZnCl₂, THF; (b) 15, PdCl₂(PPh₃)₂, THF, 81% (2 steps); (c) BnNH₂, DiBAL-H, THF, CH₂Cl₂, 86%; (d) 16, PdCl₂(PPh₃)₂, THF, DMA, 78%; (e) 17, Pd(PPh₃)₄, 1,4-dioxane, 80 °C, 61%.

Scheme 8

Synthesis of ethyl tert-butylmicrococcinate using direct C-H activation and one-pot borylation/cross-coupling of thiazoles. Reagents and conditions: (a) 18, Pd(OAc)₂, Cy-JohnPhos, Cs₂CO₃, DMF, 110 °C, 18 h, 74%; (b) CO(NH₂)₂, H₂O₂, TFAA, MeCN, 0 °C, 30 min; (c) POCl₃, toluene, DMF, rt, 6 h, 78% (2 steps); (d) NH₄OH, THF, rt, 82%; (e) Lawesson’s reagent, toluene, 2 h, 76%; (f) 20, EtOH, THF (1:1), 65%; (g) i. 19, bispinacolatodiboron, Pd₂(dba)₂, Cy-JohnPhos, KOAc, dioxane, 110 °C, 30 min; ii. K₃PO₄, dioxane, H₂O, 110 °C, 12 h, 87%.

Scheme 9

Synthesis of baringolin’s central polyheterocyclic core. Reagents and conditions: (a) tBuOK, MeOH, 65 °C, 4 days, 85%; (b) H-Thr-OBn, pyBOP, DIPEA, THF, 0 °C, 3 h, 89%; (c) Dess-Martin periodinane, CH₂Cl₂, rt, 6 h, 95%; (d) PPh₃, I₂, NEt₃, CH₂Cl₂, 0 °C to rt, 15 h, 78%; (e) 26, Pd(PPh₃)₄, 1,4-dioxane, 80 °C, 48 h, 88%; (f) HBr, AcOH, rt, 28 h, 73%; (g) (Boc)₂O, NEt₃, CH₂Cl₂, 0 °C, 4 h, 94%; (h) Tf₂O, 2,6-lutidine, DMAP, CH₂Cl₂, 0 °C to rt, 3 h, 88%; (i) 29, Pd(PPh₃)₄, DMA, 45 °C, 1 h, quant.

Scheme 10

The synthesis of the polyheterocyclic core of micrococcin P1 by Ciufolini. Reagents and conditions: (a) cat. Li₂CO₃, EtOAc, 92%; (b) NH₄OAc, EtOH then DDQ, toluene, 97%.

Scheme 11

Synthesis of amythiamicins pyridine cluster using Bohlmann-Rahtz pyridine formation. Reagents and conditions: (a) 35, nBuLi; H₂O, 91%; (b) TBAF, THF, rt, 1 h, 93%; (c) NH₄OAc, microwave, 120 °C (100 W), toluene, 30 min, 76%; (d) 36, EtOH, 60 °C; toluene, AcOH, 70 °C, 85% (93% ee). SEM = 2-(trimethylsilyl)ethoxymethyl.

Scheme 12

Synthesis of a and b series central core by Hashimoto and co-workers. Reagents and conditions: (a) Et₃N, THF, −25 °C, 71%; (b) TFA, EtOH; (c) NaBH₃CN, AcOH, EtOH, 52% (2 steps); (d) Boc₂O, DMAP, Et₃N, THF, 0 °C, 84%; (e) (S)-Boc-Ala-OH, CIP, HOAt, DIPEA, CH₂Cl₂, 93%; (f) tBuOCl, THF, −78 °C, then cat. DMAP, Et₃N, 95%. CIP = 2-chloro-1,3-dimethylimidazolidium hexafluorophosphates.

Scheme 13

Bio-inspired synthesis of b and d series polyheterocyclic cores. Reagents and conditions: (a) Ag₂CO₃, BnNH₂, DBU, pyridine, −15 °C, 1 h; then H₂O/EtOAc (1:1), 1 h, 60%; (b) DBU, EtOAc, reflux, 5 h, 50%.

Scheme 14

Bio-mimetic aza-Diels-Alder synthesis of 2,3,6-trisubstituted pyridine cores. Reagents and conditions: (a) Et₃O⁺PF₆⁻, CH₂Cl₂, 100%; (b) 46, CH₂Cl₂, then DBU, CHCl₃, 63%; (c) 47, toluene, microwave, 120 °C, 33%.

Scheme 15

Synthesis of nosiheptide core via an aza-Diels-Alder cycloaddition. Reagents and conditions: (a) toluene, 180 °C, 55%; (b) Tf₂O, Et₃N, CH₂Cl₂, 0 °C; (c) TIPSOTf, Et₃N, CH₂Cl₂,0 °C, 79% (2 steps); (d) NBS, THF/ H₂O, 97%; (e) 53, KHCO₃, THF, −40 °C; (f) TFAA, 2,6-lutidine, −20 °C, 60% (2 steps).

Scheme 16

Syntehsis of cyclothiazomycin central core hydrolysate via a [2 + 2 + 2] ruthenium-catalyzed cycloaddition. Reagents and conditions: (a) Cp*RuCl(COD), 1,2-dichloroethane, 60 °C, 82%; (b) TBAF, THF, rt, 97%; (c) John’s reagent, acetone, 0 °C to rt; (d) TFA, CH₂Cl₂, rt, 80% (2 steps). Cp* = pentamethylcyclopentadienyl. TBAF = tetrabutylammonium fluoride.