New Drug Approvals

Home » Uncategorized » Novobiocin, ノボビオシン;

Novobiocin, ノボビオシン;

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Blog Stats

  • 2,669,554 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,434 other followers

add to any

Share

Novobiocin2DCSD.svg

ChemSpider 2D Image | novobiocin | C31H36N2O11

Novobiocin

ノボビオシン;

  • Molecular FormulaC31H36N2O11
  • Average mass612.624 Da
(3R,4S,5R,6R)-5-hydroxy-6-(4-hydroxy-3-(4-hydroxy-3-(3-methylbut-2-enyl)benzamido)-8-methyl-2-oxo-2H-chromen-7-yloxy)-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate
(3R,4S,5R,6R)-5-Hydroxy-6-[(4-hydroxy-3-{[4-hydroxy-3-(3-methyl-2-buten-1-yl)benzoyl]amino}-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (non-preferred name) [ACD/IUPAC Name]
(3R,4S,5R,6R)-5-Hydroxy-6-[(4-hydroxy-3-{[4-hydroxy-3-(3-methyl-2-buten-1-yl)benzoyl]amino}-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (non-preferred name)
(3R,4S,5R,6R)-5-Hydroxy-6-[(4-hydroxy-3-{[4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoyl]amino}-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (non-preferred name)
1476-53-5 [RN]
17EC19951N
216-023-6 [EINECS]
224-321-2 [EINECS]
575
Albamycin[Trade name]
Biotexin
CAS number303-81-1
WeightAverage: 612.6243
Monoisotopic: 612.231910004
Chemical FormulaC31H36N2O11
For the treatment of infections due to staphylococci and other susceptible organisms
Novobiocin
 Novobiocin
CAS Registry Number: 303-81-1
CAS Name: N-[7-[[3-O-(Aminocarbonyl)-6-deoxy-5-C-methyl-4-O-methyl-b-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl]-4-hydroxy-3-(3-methyl-2-butenyl)benzamide
Additional Names: crystallinic acid; streptonivicin
Manufacturers’ Codes: PA-93; U-6591
Molecular Formula: C31H36N2O11
Molecular Weight: 612.62
Percent Composition: C 60.78%, H 5.92%, N 4.57%, O 28.73%
Literature References: Antibiotic substance produced by Streptomyces spheroides: Kaczka et al., J. Am. Chem. Soc. 77, 6404 (1955); Wolf, US 3000873 (1961 to Merck & Co.); Stammer, Miller; Miller; Wallick, US 3049475US 3049476US 3049534 (all 1962 to Merck & Co.). By Streptomyces niveus: Hoeksema et al., J. Am. Chem. Soc. 77, 6710 (1955); Antibiot. Chemother. 6, 143 (1956); French, US 3068221 (1962 to Upjohn). Structure: Shunk et al., J. Am. Chem. Soc. 78, 1770 (1956); Hoeksema et al., ibid.2019; Walton et al., ibid. 82, 1489 (1960). Conformation: Golding, Richards, Chem. Ind. (London) 1963, 1081. Revised configuration: O. Achmatowicz et al., Tetrahedron 32, 1051 (1976). Synthesis: Stammer, US 2925411 (1960); Walton, Spencer, US2966484 (1960 to Merck & Co.); Vaterlaus et al., Helv. Chim. Acta 47, 390 (1964). Conversion of isonovobiocin to novobiocin: Caron et al., US 2983723 (1961 to Upjohn). Antiviral activity: Chang, Weinstein, Antimicrob. Agents Chemother. 1970, 165. Efficacy in canine respiratory infections: B. W. Maxey, Vet. Med. Small Anim. Clin. 75, 89 (1980). Mechanism of action studies: Smith, Davis, J. Bacteriol. 93, 71 (1967); H. T. Wright et al., Science 213, 455 (1981); I. W. Althaus et al., J. Antibiot. 41, 373 (1988). Review: Brock in Antibiotics vol. 1, R. Gottlieb, P. Shaw, Eds. (Springer-Verlag, New York, 1967) pp 651-665; M. J. Ryan, ibid. vol. 5(pt. 1), F. E. Hahn, Ed. (1979) pp 214-234.
Properties: Pale yellow orthorhombic crystals from ethanol. Sensitive to light. d 1.3448. Dec at 152-156° (a rarer modification dec 174-178°). Acid reaction: pKa1 4.3; pKa2 9.1. [a]D24 -63.0° (c = 1 in ethanol). uv max (0.1N NaOH; 0.1N methanolic HCl; pH 7 phosphate buffer): 307; 324; 390 nm (E1%1cm 600, 390, 350 resp.). Sol in aq soln above pH 7.5. Practically insol in more acidic solns. Sol in acetone, ethyl acetate, amyl acetate, lower alcohols, pyridine. Additional soly data: Weiss et al., Antibiot. Chemother.7, 374 (1957).
pKa: pKa1 4.3; pKa2 9.1
Optical Rotation: [a]D24 -63.0° (c = 1 in ethanol)
Absorption maximum: uv max (0.1N NaOH; 0.1N methanolic HCl; pH 7 phosphate buffer): 307; 324; 390 nm (E1%1cm 600, 390, 350 resp.)
Density: d 1.3448
Derivative Type: Monosodium salt
CAS Registry Number: 1476-53-5
Trademarks: Albamycin (Pharmacia & Upjohn)
Molecular Formula: C31H35N2NaO11
Molecular Weight: 634.61
Percent Composition: C 58.67%, H 5.56%, N 4.41%, Na 3.62%, O 27.73%
Properties: Minute crystals, dec 220°. [a]D24 -38° (c = 2.5 in 95% ethanol); [a]D24 -33° (c = 2.5 in water). Freely sol in water. A 100 mg/ml soln has a pH of 7.5 and a half-life of ~30 days at 25° and several months at 4°. Soly data: Weiss et al., loc. cit. Properties: Birlova, Traktenberg, Antibiotiki 13, 997 (1968).
Optical Rotation: [a]D24 -38° (c = 2.5 in 95% ethanol); [a]D24 -33° (c = 2.5 in water)
Therap-Cat: Antibacterial.
Therap-Cat-Vet: Antimicrobial.
INGREDIENT UNII CAS INCHI KEY
Novobiocin sodium Q9S9NQ5YIY 1476-53-5 WWPRGAYLRGSOSU-RNROJPEYSA-M

Reata Pharmaceuticals Inc

Abgentis is investigating a novobiocin analog, GYR-12 (discovery), as a re-engineered, previously-marketed-but-uncompetitive (undisclosed) antibacterial compound inhibiting ATPase activity of DNA supercoiling GyrB/ParE, for the potential broad-spectrum treatment of bacterial infections, including multi-drug resistant Gram-negative infections. In April 2017, development was underway [1924695].

Novobiocin, also known as albamycin or cathomycin, is an aminocoumarin antibiotic that is produced by the actinomycete Streptomyces niveus, which has recently been identified as a subjective synonym for S. spheroides[1] a member of the order Actinobacteria. Other aminocoumarin antibiotics include clorobiocin and coumermycin A1.[2] Novobiocin was first reported in the mid-1950s (then called streptonivicin).[3][4]

It is active against Staphylococcus epidermidis and may be used to differentiate it from the other coagulase-negative Staphylococcus saprophyticus, which is resistant to novobiocin, in culture.

Novobiocin was licensed for clinical use under the tradename Albamycin (Pharmacia And Upjohn) in the 1960s. Its efficacy has been demonstrated in preclinical and clinical trials.[5][6] The oral form of the drug has since been withdrawn from the market due to lack of efficacy.[7] Novobiocin is an effective antistaphylococcal agent used in the treatment of MRSA.[8]

Mechanism of action

The molecular basis of action of novobiocin, and other related drugs clorobiocin and coumermycin A1 has been examined.[2][9][10][11][12] Aminocoumarins are very potent inhibitors of bacterial DNA gyrase and work by targeting the GyrB subunit of the enzyme involved in energy transduction. Novobiocin as well as the other aminocoumarin antibiotics act as competitive inhibitors of the ATPase reaction catalysed by GyrB. The potency of novobiocin is considerably higher than that of the fluoroquinolones that also target DNA gyrase, but at a different site on the enzyme. The GyrA subunit is involved in the DNA nicking and ligation activity.

Novobiocin has been shown to weakly inhibit the C-terminus of the eukaryotic Hsp90 protein (high micromolar IC50). Modification of the novobiocin scaffold has led to more selective Hsp90 inhibitors.[13] Novobiocin has also been shown to bind and activate the Gram-negative lipopolysaccharide transporter LptBFGC.[14][15]

Structure

Novobiocin is an aminocoumarin. Novobiocin may be divided up into three entities; a benzoic acid derivative, a coumarin residue, and the sugar novobiose.[9] X-ray crystallographic studies have found that the drug-receptor complex of Novobiocin and DNA Gyrase shows that ATP and Novobiocin have overlapping binding sites on the gyrase molecule.[16] The overlap of the coumarin and ATP-binding sites is consistent with aminocoumarins being competitive inhibitors of the ATPase activity.[17]

Structure–activity relationship

In structure activity relationship experiments it was found that removal of the carbamoyl group located on the novobiose sugar lead to a dramatic decrease in inhibitory activity of novobiocin.[17]

Biosynthesis

This aminocoumarin antibiotic consists of three major substituents. The 3-dimethylallyl-4-hydroxybenzoic acid moiety, known as ring A, is derived from prephenate and dimethylallyl pyrophosphate. The aminocoumarin moiety, known as ring B, is derived from L-tyrosine. The final component of novobiocin is the sugar derivative L-noviose, known as ring C, which is derived from glucose-1-phosphate. The biosynthetic gene cluster for novobiocin was identified by Heide and coworkers in 1999 (published 2000) from Streptomyces spheroidesNCIB 11891.[18] They identified 23 putative open reading frames (ORFs) and more than 11 other ORFs that may play a role in novobiocin biosynthesis.

The biosynthesis of ring A (see Fig. 1) begins with prephenate which is a derived from the shikimic acid biosynthetic pathway. The enzyme NovF catalyzes the decarboxylation of prephenate while simultaneously reducing nicotinamide adenine dinucleotide phosphate (NADP+) to produce NADPH. Following this NovQ catalyzes the electrophilic substitution of the phenyl ring with dimethylallyl pyrophosphate (DMAPP) otherwise known as prenylation.[19] DMAPP can come from either the mevalonic acid pathway or the deoxyxylulose biosynthetic pathway. Next the 3-dimethylallyl-4-hydroxybenzoate molecule is subjected to two oxidative decarboxylations by NovR and molecular oxygen.[20] NovR is a non-heme iron oxygenase with a unique bifunctional catalysis. In the first stage both oxygens are incorporated from the molecular oxygen while in the second step only one is incorporated as determined by isotope labeling studies. This completes the formation of ring A.

Figure 1. Biosynthetic scheme of benzamide portion of novobiocin (4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoic acid)

The biosynthesis of ring B (see Fig. 2) begins with the natural amino acid L-tyrosine. This is then adenylated and thioesterified onto the peptidyl carrier protein (PCP) of NovH by ATPand NovH itself.[21] NovI then further modifies this PCP bound molecule by oxidizing the β-position using NADPH and molecular oxygen. NovJ and NovK form a heterodimer of J2K2 which is the active form of this benzylic oxygenase.[22] This process uses NADP+ as a hydride acceptor in the oxidation of the β-alcohol. This ketone will prefer to exist in its enol tautomer in solution. Next a still unidentified protein catalyzes the selective oxidation of the benzene (as shown in Fig. 2). Upon oxidation this intermediate will spontaneously lactonize to form the aromatic ring B and lose NovH in the process.

Figure 2. Biosynthesis of 3-amino-4,7-dihydroxy-2H-chromen-2-one component of novobiocin (ring B)

The biosynthesis of L-noviose (ring C) is shown in Fig. 3. This process starts from glucose-1-phosphate where NovV takes dTTP and replaces the phosphate group with a dTDP group. NovT then oxidizes the 4-hydroxy group using NAD+. NovT also accomplishes a dehydroxylation of the 6 position of the sugar. NovW then epimerizes the 3 position of the sugar.[23] The methylation of the 5 position is accomplished by NovU and S-adenosyl methionine (SAM). Finally NovS reduces the 4 position again to achieve epimerization of that position from the starting glucose-1-phosphate using NADH.

Figure 3. Biosynthesis of L-noviose component of novobiocin (ring C)

Rings A, B, and C are coupled together and modified to give the finished novobiocin molecule. Rings A and B are coupled together by the enzyme NovL using ATP to diphosphorylate the carboxylate group of ring A so that the carbonyl can be attacked by the amine group on ring B. The resulting compound is methylated by NovO and SAM prior to glycosylation.[24] NovM adds ring C (L-noviose) to the hydroxyl group derived from tyrosine with the loss of dTDP. Another methylation is accomplished by NovP and SAM at the 4 position of the L-noviose sugar.[25] This methylation allows NovN to carbamylate the 3 position of the sugar as shown in Fig. 4 completing the biosynthesis of novobiocin.

Figure 4. Completed biosynthesis of novobiocin from ring systems AB, and C.
CLIP

CLIP

CLIP

CLIP

str1-1

PATENT

US-20190241599

Novel co-crystal forms of novobiocin and its analogs and proline, processes for their preparation and compositions comprising them are claimed. Also claims are methods for inhibiting heat shock protein 90 and treating or preventing neurodegenerative disorders, such as diabetic peripheral neuropathy.

References

  1. ^ Lanoot B, Vancanneyt M, Cleenwerck I, Wang L, Li W, Liu Z, Swings J (May 2002). “The search for synonyms among streptomycetes by using SDS-PAGE of whole-cell proteins. Emendation of the species Streptomyces aurantiacus, Streptomyces cacaoi subsp. cacaoi, Streptomyces caeruleus and Streptomyces violaceus”. International Journal of Systematic and Evolutionary Microbiology52 (Pt 3): 823–9. doi:10.1099/ijs.0.02008-0PMID 12054245.
  2. Jump up to:a b Alessandra da Silva Eustáquio (2004) Biosynthesis of aminocoumarin antibiotics in Streptomyces: Generation of structural analogues by genetic engineering and insights into the regulation of antibiotic production. DISSERTATION
  3. ^ Hoeksema H.; Johnson J. L.; Hinman J. W. (1955). “Structural studies on streptonivicin, a new antibiotic”. J Am Chem Soc77 (24): 6710–6711. doi:10.1021/ja01629a129.
  4. ^ Smith C. G.; Dietz A.; Sokolski W. T.; Savage G. M. (1956). “Streptonivicin, a new antibiotic. I. Discovery and biologic studies”. Antibiotics & Chemotherapy6: 135–142.
  5. ^ Raad I, Darouiche R, Hachem R, Sacilowski M, Bodey GP (November 1995). “Antibiotics and prevention of microbial colonization of catheters”Antimicrobial Agents and Chemotherapy39 (11): 2397–400. doi:10.1128/aac.39.11.2397PMC 162954PMID 8585715.
  6. ^ Raad II, Hachem RY, Abi-Said D, Rolston KV, Whimbey E, Buzaid AC, Legha S (January 1998). “A prospective crossover randomized trial of novobiocin and rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2”. Cancer82 (2): 403–11. doi:10.1002/(SICI)1097-0142(19980115)82:2<412::AID-CNCR22>3.0.CO;2-0PMID 9445199.
  7. ^ “Determination That ALBAMYCIN (Novobiocin Sodium) Capsule, 250 Milligrams, Was Withdrawn From Sale for Reasons of Safety or Effectiveness”The Federal Register. 19 January 2011.
  8. ^ Walsh TJ, Standiford HC, Reboli AC, John JF, Mulligan ME, Ribner BS, Montgomerie JZ, Goetz MB, Mayhall CG, Rimland D (June 1993). “Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome”Antimicrobial Agents and Chemotherapy37 (6): 1334–42. doi:10.1128/aac.37.6.1334PMC 187962PMID 8328783.
  9. Jump up to:a b Maxwell A (August 1993). “The interaction between coumarin drugs and DNA gyrase”. Molecular Microbiology9 (4): 681–6. doi:10.1111/j.1365-2958.1993.tb01728.xPMID 8231802.
  10. ^ Maxwell A (February 1999). “DNA gyrase as a drug target”. Biochemical Society Transactions27 (2): 48–53. doi:10.1042/bst0270048PMID 10093705.
  11. ^ Lewis RJ, Tsai FT, Wigley DB (August 1996). “Molecular mechanisms of drug inhibition of DNA gyrase”. BioEssays18 (8): 661–71. doi:10.1002/bies.950180810PMID 8760340.
  12. ^ Maxwell A, Lawson DM (2003). “The ATP-binding site of type II topoisomerases as a target for antibacterial drugs”. Current Topics in Medicinal Chemistry3 (3): 283–303. doi:10.2174/1568026033452500PMID 12570764.
  13. ^ Yu XM, Shen G, Neckers L, Blake H, Holzbeierlein J, Cronk B, Blagg BS (September 2005). “Hsp90 inhibitors identified from a library of novobiocin analogues”. Journal of the American Chemical Society127 (37): 12778–9. doi:10.1021/ja0535864PMID 16159253.
  14. ^ Mandler MD, Baidin V, Lee J, Pahil KS, Owens TW, Kahne D (June 2018). “Novobiocin Enhances Polymyxin Activity by Stimulating Lipopolysaccharide Transport”Journal of the American Chemical Society140 (22): 6749–6753. doi:10.1021/jacs.8b02283PMC 5990483PMID 29746111.
  15. ^ May JM, Owens TW, Mandler MD, Simpson BW, Lazarus MB, Sherman DJ, Davis RM, Okuda S, Massefski W, Ruiz N, Kahne D (December 2017). “The Antibiotic Novobiocin Binds and Activates the ATPase That Powers Lipopolysaccharide Transport”Journal of the American Chemical Society139 (48): 17221–17224. doi:10.1021/jacs.7b07736PMC 5735422PMID 29135241.
  16. ^ Tsai FT, Singh OM, Skarzynski T, Wonacott AJ, Weston S, Tucker A, Pauptit RA, Breeze AL, Poyser JP, O’Brien R, Ladbury JE, Wigley DB (May 1997). “The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin”. Proteins28 (1): 41–52. doi:10.1002/(sici)1097-0134(199705)28:1<41::aid-prot4>3.3.co;2-bPMID 9144789.
  17. Jump up to:a b Flatman RH, Eustaquio A, Li SM, Heide L, Maxwell A (April 2006). “Structure-activity relationships of aminocoumarin-type gyrase and topoisomerase IV inhibitors obtained by combinatorial biosynthesis”Antimicrobial Agents and Chemotherapy50 (4): 1136–42. doi:10.1128/AAC.50.4.1136-1142.2006PMC 1426943PMID 16569821.
  18. ^ Steffensky M, Mühlenweg A, Wang ZX, Li SM, Heide L (May 2000). “Identification of the novobiocin biosynthetic gene cluster of Streptomyces spheroides NCIB 11891”Antimicrobial Agents and Chemotherapy44 (5): 1214–22. doi:10.1128/AAC.44.5.1214-1222.2000PMC 89847PMID 10770754.
  19. ^ Pojer F, Wemakor E, Kammerer B, Chen H, Walsh CT, Li SM, Heide L (March 2003). “CloQ, a prenyltransferase involved in clorobiocin biosynthesis”Proceedings of the National Academy of Sciences of the United States of America100 (5): 2316–21. Bibcode:2003PNAS..100.2316Pdoi:10.1073/pnas.0337708100PMC 151338PMID 12618544.
  20. ^ Pojer F, Kahlich R, Kammerer B, Li SM, Heide L (August 2003). “CloR, a bifunctional non-heme iron oxygenase involved in clorobiocin biosynthesis”. The Journal of Biological Chemistry278 (33): 30661–8. doi:10.1074/jbc.M303190200PMID 12777382.
  21. ^ Chen H, Walsh CT (April 2001). “Coumarin formation in novobiocin biosynthesis: beta-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 NovI”. Chemistry & Biology8 (4): 301–12. doi:10.1016/S1074-5521(01)00009-6PMID 11325587.
  22. ^ Pacholec M, Hillson NJ, Walsh CT (September 2005). “NovJ/NovK catalyze benzylic oxidation of a beta-hydroxyl tyrosyl-S-pantetheinyl enzyme during aminocoumarin ring formation in novobiocin biosynthesis”. Biochemistry44 (38): 12819–26. CiteSeerX 10.1.1.569.1481doi:10.1021/bi051297mPMID 16171397.
  23. ^ Thuy TT, Lee HC, Kim CG, Heide L, Sohng JK (April 2005). “Functional characterizations of novWUS involved in novobiocin biosynthesis from Streptomyces spheroides”. Archives of Biochemistry and Biophysics436 (1): 161–7. doi:10.1016/j.abb.2005.01.012PMID 15752721.
  24. ^ Pacholec M, Tao J, Walsh CT (November 2005). “CouO and NovO: C-methyltransferases for tailoring the aminocoumarin scaffold in coumermycin and novobiocin antibiotic biosynthesis”. Biochemistry44 (45): 14969–76. doi:10.1021/bi051599oPMID 16274243.
  25. ^ Freel Meyers CL, Oberthür M, Xu H, Heide L, Kahne D, Walsh CT (January 2004). “Characterization of NovP and NovN: completion of novobiocin biosynthesis by sequential tailoring of the noviosyl ring”. Angewandte Chemie43 (1): 67–70. doi:10.1002/anie.200352626PMID 14694473.

External links

Novobiocin
Novobiocin2DCSD.svg
Space-filling model of the novobiocin molecule
Clinical data
AHFS/Drugs.com International Drug Names
Routes of
administration
intravenous
ATCvet code
Pharmacokinetic data
Bioavailability negligible oral bioavailability
Metabolism excreted unchanged
Elimination half-life 6 hours
Excretion renal
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard 100.005.589 Edit this at Wikidata
Chemical and physical data
Formula C31H36N2O11
Molar mass 612.624 g·mol−1
3D model (JSmol)

Novobiocin calcium.png

4309-70-0  CAS

calcium;7-[(2R,3R,4S,5R)-4-carbamoyloxy-3-hydroxy-5-methoxy-6,6-dimethyloxan-2-yl]oxy-3-[[4-hydroxy-3-(3-methylbut-2-enyl)benzoyl]amino]-8-methyl-2-oxochromen-4-olate

///////// Novobiocin, ノボビオシン  , Antibacterial, Antimicrobial,  crystallinic acid, streptonivicin,

Manufacturers’ Codes: PA-93; U-6591

History

Novobiocin is a coumarin antibiotic obtained from Streptomyces niveus and other Streptomyces species. Novobiocin is useful primarily in infections involving staphylococci, and other gram-positive organisms. It acts by inhibiting the initiation of DNA replication in bacterial and mammanlian cells. Evidences indicated that Novobiocin blocks prokaryotic DNA gyrase and eukaryotic II topoisomerase, enzymes that relax super-coiled DNA and are crucial for DNA replication.1

Novobiocin

UIPAC Name 4-Hydroxy-3-4-hydroxy-3-(3-methylbut-2-enyl)benzamido-8-methylcoumarin-7-yl 3-O-carbamoyl-5,5-di-C-methyl-α-l-lyxofuranoside
CAS Number 303-81-1
Molecular Mass 612.624 g / mol
Chemical Formular C31H36N2O11

Biosynthesis

The substituted coumarin (ring B, red) and the 4-OH benzoyl moiety (ring A, aqua) in novobiocin were derived from Image-Tyr based on earlier labeling studies. β-OH-Tyr is proposed to be a common intermediate in these two biosynthetic pathways.2

NovH is a Image-Tyr specific didomain NRPS that generates the Image-tyrosyl-S-NovH intermediate. NovH, isolated from E. coli is primed by a PPTase with CoA. The A domain activates Image-Tyr as Image-tyrosyl-AMP and then transfers the Image-tyrosyl group to the HS-pant-PCP domain of NovH through thioester formation.3

Image-tyrosyl-S-NovH is then function as a cytochrome P450 monooxygenase that hydroxylates the β-carbon of the tethered Image-tyrosyl group on NovH. While the substrate Image-tyrosyl-S-NovH provides two electrons for a single round of the hydroxylation reaction, the other two electrons needed to reduce the oxygen atom are provided by NADPH via two-electron transfer effected by electron transfer proteins ferrodoxin (Fd) and ferrodoxin reductase (Fd Red).3 The electron transfer route is from NADPH→FAD in Fd Red→Fe–S center in Fd→Heme in NovI→oxygen.

Both NovJ and NovK are similar to 3-keto-ACP reductase and they may form a heterodimer and operate in the reverse direction to oxidize 3-OH to 3-keto. NovO is similar to some quinone C-methyltransferases 3 but the timing of methylation is not clear. NovC resembles flavin-dependent monooxygenases (35 and 32% similarity to dimethylaniline and cyclohexanone monooxygenases, respectively) 3 and is proposed to hydroxylate the ortho position of the phenyl ring. The nucleophilic attack of the ortho hydroxyl group on the thioester carbonyl center would release the coumarin ring and regenerate NovH. Ring B is then synthesized.

Synthesis

Mechanism of action

E.Coli DNA gyrase utilizes ATP to catalyze the negative supercoiling, or under-twisting, of duplex DNA. The energy coupling components of the supercoiling reaction includes 1) the DNA-dependent hydrolysis that converts ATP to ADP and Pi, and 2) the gyrase cleavage reaction that targets the specified DNA site. The two activities are induced by treating the stable gyrase-DNA complex trapped by the inihibitor oxolinic acid with sodium dodecyl sulfate (SDS or Sulphate). 4 Novobiocin competes with ATP in the ATPase and supercoiling assays, hence Novobiocin prevents the ATP from shifting the primary cleavage site on ColE1 DNA by places the site of action of the antibiotics at a reaction step prior to ATP hydrolysis and blocks the binding of ATP. 4 Such a simple mechanism of action represents for all effects of the drugs on DNA gyrase.

Clinical Use

Due to factors as low solubility, poor pharmacokinetics, and limited activity agasinst Gram-negative bacteria, the clinical usage of Novobiocin is not achieved. 5 Therefore, it is of interest to study the novobiocin biosynthetic pathway in order to generate analogs with enhanced solubility and pharmacokinetic properties while maintaining the gyrase inhibitory properties.

References

1 J.C. D’Halluin, M. Milleville, and P. Boulanger. “Effect of Novobiocin on adenovirus DNA synthesis and encapsidation”. Nucleic Acids Research 1980; 8: 1625-1641

2 M. Steffensky, S.M. Li and L. Heide, “Cloning, overexpression, and purification of novobiocic acid synthetase from Streptomyces spheroides ” NCIB 11891. J. Biol. Chem. 275 (2000), pp. 21754–21760.

3 Huawei Chen and Christopher T. Walsh, “Coumarin formation in novobiocin biosynthesis: β-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 NovI” Chemistry and Biology; 2001; 8: 301-312

4 K. Scheirer and N. P. Higgins. “The DAN Cleavage Reaction of DNA Gyrase ” The Journal of Biological Chemistry; 1997; 272 (43): 27202-27209

5 N Pi, C. L. F. Meyers, M. Pacholec, C. T. Walsh, and J. A. Leary. “Mass spectrometric characterization of a three-enzyme tandem reacton for assembly and modification of the novobiocin skeleton” PNAS 2004;101;10036-10041


1 Comment

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,434 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

View Full Profile →

TWITTER

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: