Ramoplanin

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Ramoplanin
Structure of Ramoplanin A2, with the variable acyl sidechain in blue.
Clinical data
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
Identifiers
JSmol)
  • C[C@@H]1C(=O)N[C@H](C(=O)O[C@@H]([C@@H](C(=O)N[C@@H](C(=O)N[C@@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N1)CC(C)C)c2ccc(cc2)O)[C@@H](C)O)c3ccc(cc3)O[C@@H]4[C@H]([C@H]([C@@H]([C@H](O4)CO)O)O)O[C@@H]5[C@H]([C@H]([C@@H]([C@H](O5)CO)O)O)O)CCCN)Cc6ccccc6)[C@H](C)O)c7ccc(cc7)O)c8ccc(cc8)O)[C@@H](C)O)CCCN)c9ccc(cc9)O)NC(=O)[C@H](CC(=O)N)NC(=O)/C=C\C=C\CC(C)C)C(=O)N)c1ccc(c(c1)Cl)O
  • InChI=1S/C119H154ClN21O40/c1-54(2)17-11-9-14-22-82(153)127-77(50-81(123)152)107(166)141-93-99(101(124)160)180-117(176)92(66-33-44-78(151)72(120)49-66)140-102(161)56(5)126-105(164)75(47-55(3)4)128-83(154)51-125-108(167)87(61-23-34-67(147)35-24-61)136-111(170)86(59(8)146)134-113(172)89(65-31-42-71(43-32-65)177-119-100(97(158)95(156)80(53-143)179-119)181-118-98(159)96(157)94(155)79(52-142)178-118)135-104(163)73(20-15-45-121)129-106(165)76(48-60-18-12-10-13-19-60)131-109(168)84(57(6)144)133-114(173)90(63-27-38-69(149)39-28-63)138-115(174)91(64-29-40-70(150)41-30-64)137-110(169)85(58(7)145)132-103(162)74(21-16-46-122)130-112(171)88(139-116(93)175)62-25-36-68(148)37-26-62/h9-14,18-19,22-44,49,54-59,73-77,79-80,84-100,118-119,142-151,155-159H,15-17,20-21,45-48,50-53,121-122H2,1-8H3,(H2,123,152)(H2,124,160)(H,125,167)(H,126,164)(H,127,153)(H,128,154)(H,129,165)(H,130,171)(H,131,168)(H,132,162)(H,133,173)(H,134,172)(H,135,163)(H,136,170)(H,137,169)(H,138,174)(H,139,175)(H,140,161)(H,141,166)/b11-9+,22-14-/t56-,57+,58-,59-,73-,74-,75+,76+,77+,79-,80-,84+,85-,86-,87+,88-,89+,90-,91+,92+,93+,94-,95-,96+,97+,98+,99+,100+,118-,119+/m1/s1 ☒N
  • Key:KGZHFKDNSAEOJX-WIFQYKSHSA-N ☒N
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Ramoplanin (

Gram-positive bacteria.[2]

Mechanism

It exerts its bacteriocidal effect by inhibiting cell wall biosynthesis, acting by inhibiting the transglycosylation step of peptidoglycan synthesis.[3] Ramoplanin specifically binds to and sequesters lipid intermediates I and II, preventing intracellular glycosyltransferase (MurG) and other steps of the peptidoglycan assembly system.[4]

Uses

Its development has been fast-tracked by the

Clostridium difficile infection of the gastrointestinal tract,[5] Unlike vancomycin, it is absorbed in the gastrointestinal tract, although it is unstable in the bloodstream, so can be taken only orally against Clostridium difficile infections of the gastrointestinal tract.[6][7][8]

Ramoplanin is "particularly useful" in cases E. faecalis no matter its sensitivity to vancomycin.[2]

Chemistry

Ramoplanin is a mixture of three related compounds that vary in the acyl group on the Asn N-terminus, with the most abundant form (shown in the infobox) being A2.[4]: Fig. 1 

Synthesis

Biosynthesis

The biosynthesis is performed by a 33-gene cluster containing

nonribosomal peptide synthetase genes and supporting enzymes for amino acid and fatty acid synthesis, revealed by sequencing of the producer strain in 2002. Initial investigation into the functions of individual genes were conducted in 2012.[9]

Total synthesis

The general synthesis of Ramoplanin A1, A2 and A3 aglycons entails the preparation of residues 3-9 (heptapeptide 15), pentadepsipeptide 26 (residues 1, 2 and 15–17) along with pentapeptide 34 (residues 10–14), subsequent coupling, and cyclization to create the 49-membered aglycon core of the compound.[10] The synthesis of Ramoplanin A2 aglycon and A3 aglycon are very similar to scheme 6, where ramoplanin A1 aglycon requires the corresponding acyl group and DMF, while ramoplanin A3 aglycon synthesis requires both Bu
4NF, i-PrOH, and then treatment with the acyl group and DMF.[4]

  • Ramoplanin A2 Aglycon Synthesis
  • 1 - Synthesis of Hpg3-Phe9 Subunit
    1 - Synthesis of Hpg3-Phe9 Subunit
  • 2 - Fmoc-L-HAsn(Trt)-Obn Preparation
    2 - Fmoc-L-HAsn(Trt)-Obn Preparation
  • 3 - Synthesis of Depsipeptide subunit
    3 - Synthesis of Depsipeptide subunit
  • 4 - Synthesis of Orn10-Gly14 Subunit
    4 - Synthesis of Orn10-Gly14 Subunit
  • 5 - Preparation of acyl group
    5 - Preparation of acyl group
  • 6 - Deprotection
    6 - Deprotection

References

  1. S2CID 6026698
    .
  2. ^
    ISBN 978-0-08-045044-5
    , retrieved 2022-06-04
  3. PMID 16880924
    .
  4. ^
    PMID 15175429
    .
  5. S2CID 12881565
    .
  6. PMID 17373167
    .
  7. PMID 17644040
    .
  8. PMID 18177219
    .
  9. PMID 22222159
    .
  10. PMID 12580615
    .
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