303-81-1 Usage
Uses
Used in Pharmaceutical Industry:
Novobiocin is used as an antibiotic for the treatment of infections caused by Gram-positive bacteria, particularly Staphylococcus epidermis. It exhibits broad-spectrum Gram-positive activity and has been used clinically under the trade name Albamycin.
Used in Antimicrobial Applications:
Novobiocin is used as an antimicrobial agent for the eradication of methicillin-resistant Staphylococcus aureus (MRSA) and other resistant microorganisms. It acts as a potent inhibitor of bacterial DNA gyrase and a competitive inhibitor of the ATPase reaction catalyzed by GyrB.
Used in Cancer Therapy:
Novobiocin has been applied in cancer therapy, where it has shown potential benefits in treating various types of cancer. Its use in this field is still under investigation and development.
Chemical Properties:
Novobiocin is a light-yellow to white antibiotic produced by Streptomyces niveus. It is available as calcium and sodium salts.
Originator
Albamycin,Upjohn,US,1956
Manufacturing Process
The preparation of novobiocin by fermentation is described in US Patent 3,049,534 as follows: A medium containing 2% soybean meal, 1% dextrose, 0.25% sodium chloride and 0.75% distiller's solubles was made up in tap water. About 25 ml of the prepared medium was placed in a 75 ml vial and sterilized by heating at 120°C for 20 minutes. The sterilized medium was then inoculated with a vegetative culture of Streptomyces spheroides MA-319 (NRRL 2449), and the vial loosely stoppered with cotton. The vial was then placed on a shaking machine with an amplitude of 1? inches at 28°C for 6 days. At the end of this fermentation time, the fermented broth was assayed using the cylinder-plate method with Bacillus megatherium ATCC 9885 as the assay organism and found to have an activity of 600 units/ml or 30 mcg/ml of novobiocin. The production of larger quantities of novobiocin by submerged fermentation in suitable tanks is also described in US Patent 3,049,534.
The preparation of novobiocin by a synthetic route is described in US Patent 2,966,484, as well as in US Patent 2,925,411.
Therapeutic Function
Antibiotic
World Health Organization (WHO)
Novobiocin, an antibiotic with a narrow spectrum of activity, was
introduced in 1956. Its use was subsequently associated with serious adverse
effects including blood dyscrasias. In view of its toxicity there are no current valid
indications for its use. Although preparations containing novobiocin may remain
available in some countries it has largely lapsed into disuse.
Antimicrobial activity
Novobiocin is active against some of these bacteria, such as S. aureus (including beta-lactamase-producing strains) and the pneumococcus. Its MIC against strains of MRSA is r 0.25 mg/L, and against such strains when combined with rifampicin it shows neither synergy nor antagonism, but emergence of resistance to either agent seems to be prevented. Streptococcus pyogenes is much less susceptible and Streptococcus viridans strains vary in their sensitivity. Enterococcus faecalis is usually moderately resistant, but E. faecium, including multiresistant strains, is susceptible. Gram-positive bacilli, such as Bacillus anthracis, Clostridium tetani, C. perfringens, and Corynebacterium diphtheriae, are novobiocin susceptible. S. saprophyticus is intrinsically resistant due to alteration in the GyrB gene.
Hazard
May have damaging side effects.
Mechanism of action
Novobiocin inhibits DNA and bacterial protein synthesis by binding to the GyrB subunit of DNA topoisomerase II (gyrase), an enzyme which is associated with the supercoiling of DNA. Although quinolones also target DNA gyrase, the binding site for quinolones is different. Like other aminocoumarin antibiotics, novobiocin acts as a competitive inhibitor of the ATPase reaction catalyzed by GyrB. There is also activity against topoisomerase IV .
Pharmacokinetics
Novobiocin is well absorbed from the alimentary tract. After a single oral dose of 0.5 g to adults, a peak serum level of 10–20 mg/l levels may persist for 24 h or longer. Doubling the dose doubles the serum concentrations. If a dose of 0.5 g is administered orally every 6 h, there is often some accumulation, and after four doses the peak serum level may reach 100 mg/l. When an oral dose of 0.5 g novobiocin was given orally twice daily to adult volunteers for 27 doses, the mean serum concentration prior to dose 27 was 21.6 mg/l; this rose to a mean peak serum level 2 h after the dose of 55.5 mg/l. When oral rifampicin (300 mg 12-hourly) was given concomitantly, the comparative values before and after the last dose were 6.9 and 49.2 mg/l, respectively. Similarly, novobiocin levels were lower when rifampicin was co-administered than when novobiocin was given alone at 8 h (7.9 versus 21.6 mg/l) and at 12 h after the 27th dose (3.0 versus 16.0 mg/l). The half-life of novobiocin (5.85 h) was reduced to 2.66 h when administered in combination with rifampicin.
Clinical Use
Novobiocin formerly had a role in the treatment of staphylococcal infections. With the advent of the penicillinase-resistant penicillins and other anti-staphylococcal agents, novobiocin is no longer used for this indication, except perhaps as an adjunct to other drugs for the treatment of methicillin-resistant staphylococcal infections. For instance, novobiocin/sodium fusidate and novobiocin/rifampicin combinations have been used successfully to treat staphylococcal infections of this nature.
Veterinary Drugs and Treatments
Novobiocin is approved as a single agent and in combination with
penicillin G for use in dry dairy cattle as a mastitis tube. Novobiocin
is available in combination with tetracycline and prednisolone for
oral use in dogs.
Check Digit Verification of cas no
The CAS Registry Mumber 303-81-1 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 3,0 and 3 respectively; the second part has 2 digits, 8 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 303-81:
(5*3)+(4*0)+(3*3)+(2*8)+(1*1)=41
41 % 10 = 1
So 303-81-1 is a valid CAS Registry Number.
InChI:InChI=1/C31H36N2O11/c1-14(2)7-8-16-13-17(9-11-19(16)34)27(37)33-21-22(35)18-10-12-20(15(3)24(18)42-28(21)38)41-29-23(36)25(43-30(32)39)26(40-6)31(4,5)44-29/h7,9-13,23,25-26,29,34-36H,8H2,1-6H3,(H2,32,39)(H,33,37)/t23-,25+,26-,29-/m1/s1
303-81-1Relevant articles and documents
CHEMOSELECTIVE ENRICHMENT FOR COMPOUND ISOLATION
-
Paragraph 0284; 0288, (2014/05/07)
Chemoselective isolation of aliphatic hydroxyl group-containing and aromatic hydroxyl group-containing compounds is accomplished via formation of polymeric siloxyl ethers. Chemoselective release of aliphatic hydroxyl group-containing and aromatic hydroxyl group-containing compounds from polymeric siloxyl reagents is described.
Synthesis and biological evaluation of novobiocin analogues as potential heat shock protein 90 inhibitors
Gunaherath, G.M. Kamal B.,Marron, Marilyn T.,Wijeratne, E.M. Kithsiri,Whitesell, Luke,Gunatilaka, A.A. Leslie
, p. 5118 - 5129 (2013/09/02)
Recent studies have shown that novobiocin (NB), a member of the coumermycin (CA) family of antibiotics with demonstrated DNA gyrase inhibitory activity, inhibits Heat shock protein 90 (HSP90) by binding weakly to a putative ATP-binding site within its C-terminus. To develop more potent HSP90 inhibitors that target this site and to define structure-activity relationships (SARs) for this class of compounds, we have synthesized twenty seven 3-amido-7- noviosylcoumarin analogues starting from NB and CA. These were evaluated for evidence of HSP90 inhibition using several biological assays including inhibition of cell proliferation and cell cycle arrest, induction of the heat shock response, inhibition of luciferase-refolding in vitro, and depletion of the HSP90 client protein c-erbB-2/HER-2/neu (HER2). This SAR study revealed that a substantial increase in biological activity can be achieved by introduction of an indole-2-carboxamide group in place of 4-hydroxy-isopentylbenzamido group at C-3 of NB in addition to removal/derivatization of the 4-hydroxyl group from the coumarin ring. Methylation of the 4-hydroxyl group in the coumarin moiety moderately increased biological activity as shown by compounds 11 and 13. Our most potent new analogue 19 demonstrated biological activities consistent with known HSP90-binding agents, but with greater potency than NB.
Taming of a superbase for selective phenol desilylation and natural product isolation
Trader, Darci J.,Carlson, Erin E.
, p. 7349 - 7355 (2013/08/23)
Hydroxyl moieties are highly prevalent in natural products. We previously reported a chemoselective strategy for enrichment of hydroxyl-functionalized molecules by formation of a silyl ether bond to a resin. To generate smaller pools of molecules for analysis, we developed cleavage conditions to promote stepwise release of phenolic silyl ethers followed by aliphatic silyl ethers with a "tamed" version of the superbase 1,1,3,3-tetramethylguanadine. We demonstrate this as a general strategy for selective deprotection of phenolic silyl ethers under neutral conditions at room temperature.
Characterization of NovP and NovN: Completion of Novobiocin Biosynthesis by Sequential Tailoring of the Noviosyl Ring
Meyers, Caren L. Freel,Oberthuer, Markus,Xu, Hui,Heide, Lutz,Kahne, Daniel,Walsh, Christopher T.
, p. 67 - 70 (2007/10/03)
Two steps forward: The glycosylated aminocoumarin antibiotic novobiocin (1) is produced by. Streptomyces spheroides and inhibits the bacterial type II topoisomerase DNA gyrase. The sugar-tailoring enzymes NovP and NovN that catalyze the final two steps in novobiocin biosynthesis were overproduced in Escherichia coli and characterized as a methyltransferase and carbamoyltransferase, respectively.
Steroid derived antibiotics
-
, (2008/06/13)
A series of novel steroid derivatives are described. The steroid derivatives are antibacterial agents. The steroid derivatives also act to sensitize bacteria to other antibiotics including erythromycin and novobiocin.
Steroid derived antibiotics
-
, (2008/06/13)
A series of novel steroid derivatives are described. The steroid derivatives are antibacterial agents. The steroid derivatives also act to sensitize bacteria to other antibiotics including erythromycin and novobiocin.
Steroid derived antibiotics
-
, (2008/06/13)
A series of novel steroid derivatives are described. The steroid derivatives are antibacterial agents. The steroid derivatives also act to sensitize bacteria to other antibiotics including erythromycin and novobiocin.
Method for treating inflammation
-
, (2008/06/13)
A method of treating inflammation comprising topical administration to mammals suffering from an inflammatory condition not associated with amicrobial component, employing selected antibiotics as the anti-inflammatory agent.
