Demystifying The Magic Methyl Effect
Demystifying the Magic Methyl EffectPatricia ZhangMacMillan Group MeetingJune 11, 2015
Demystifying the Magic Methyl Effect
Demystifying the Magic Methyl Effect When is the Magic Methyl Effect in play?The so-called Magic Methyl Effect: (a general definition)"a rare but welcome phenomenon" where installation of a methylgroup on a drug candidate leds to an increase in potency a large emphasis on the drastic change in conformation, hence, binding vastatinIC 50 HMG-CoAR 5.6 nMHOHMeMelovastatinIC 50 HMG-CoAR 2.2 nMsimvastatinIC 50 HMG-CoAR 0.9 nM"The methyl group, so often considered as chemically inert, is able to alter deeplythe pharmacological properties of a molecule."Bazzini, P.; Wermuth, C. G. In The Practice of Medicinal Chemistry; Academic Press: San Diego, 2008; pp 431-418."In comparison to its importance to the pharmaceutical industry, the methyl group is,in our opinion, underrepresented in recent synthetic chemistry.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect The Benign Methyl Group - DNA vs NANNHRNANH 2ONguanineNH 2NNNHNH 2NHOOcytosineNHNNadenine CH/π-interaction has been studied for Me and purine oligonucleotides to show appreciablechange in DNA strand stiffness (important for enzyme recognition of DNA)Nishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahedron 1995, 51, 8665.Umezawa, Y.; Nishio, M. Nucleic Acids Res. 2002, 30, 2183.
Demystifying the Magic Methyl Effect The Benign Methyl Group - DNA vs RNAOObaseMeNHNHNHHOOOHthymineOOPO- yellow adenineO-DNANHHH/OH gray thymineOuracilRNA red CH/π-interactionNH 2ONNHguanineNNNHNNH 2NH 2NHOcytosineNHNNadenine CH/π-interaction has been studied for Me and purine oligonucleotides to show appreciablechange in DNA strand stiffness (important for enzyme recognition of DNA)Nishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahedron 1995, 51, 8665.Umezawa, Y.; Nishio, M. Nucleic Acids Res. 2002, 30, 2183.
Demystifying the Magic Methyl Effect The Benign Methyl Group - � (acceptor)HVia CH/π-interactions: methyl groups have a greaterchance to be involved in an interaction compared to OHdue to: more (three) hydrogens multiple simultaneous interactions possible additive free energy effectsNishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahedron 1995, 51, 8665.Umezawa, Y.; Nishio, M. Nucleic Acids Res. 2002, 30, 2183.
Demystifying the Magic Methyl Effect Modes of Actiona combination of.SolubilityConformationBinding InteractionsMetabolismlater.Current Synthetic Methods
Demystifying the Magic Methyl Effect Modes of Actiona combination of.SolubilityConformationBinding InteractionsMetabolismlater.Current Synthetic Methods
Demystifying the Magic Methyl Effect SolubilityGeneral solubility for increased bioavailabilityLipophilicityHydrophilic Effect"lipid loving", 00g H 2OLog P 2.13MeMeMeisobutanol5g/100g H 2OOHtert-butanolmiscibleLog P 2.69Log P is logarithm of the partitioncoefficient between n-octanol and waterMe important for crossing biomembranes toget to target tissues and for transportthrough bloodstreamMeMeOHMeMeMeMe H 2OOHn-pentanol2.4g/100g H 2OMeMeMeMeMeOH2-pentanol4.9g/100g H 2OMeOHneopentanol12.2g/100g H 2O fewer water molecules needed to beorganized, entropic gain with "globular" 3shape more negative ΔG desolvation whentransitioning from aqueous to membraneBarreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect Lipophilicity to increase bioavailabilityPlacement of methyl groups is important:MeHOHOONMeOmorphinestructure elucidated bySir Robert RobinsonONHHHOONHHOnormorphine6-fold reduction in in vivoanalgesic activityMeHHOcodeine3-fold reduction in in vivoanalgesic activity, 200-foldreduction in receptor affinity dominant ionic interactions for drug catalyticsite still maintained more polar nitrogen moiety, harder to passthrough blood-brain barrierBarreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect Lipophilicity to increase bioavailabilityPlacement of methyl groups is important:TM transmembrane domainHisVI-17TM-VIHNNOHTM IIIOH H-bond interactionOAspIII-08 van der Waals interactionsHOHO ionic interaction with aminiumcation and carboxylateNH-bond donorMeHNTM VTrpV-10PheV-13Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect Lipophilicity to increase bioavailabilityPlacement of methyl groups is important:TM transmembrane domainTM-VIHisVI-17NNOH dominant ionic interactions fordrug catalytic site still maintainedHTM IIIOOAspIII-08HOHON weaker H-bond interactioncauses 200-fold reduction inreceptor bindingMeweak H-bond acceptorMeHNTM V codeine gets metabolized tomorphineTrpV-10PheV-13Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect Lipophilicity to increase bioavailabilityPlacement of methyl groups is important:TM transmembrane domainHisVI-17TM-VIHNMeNOTM IIIOH H-bond interactionOAspIII-08HOHONH-bond donorMe heterocodeine has a 2-foldincrease in in vivo activity methyl allyic ether aids in solubility,hence, passage through central nervoussystemHNTM VTrpV-10PheV-13Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect Free energy of desolvation more -CH3 groups leads to more spontaneous transfer from aqueous to protein layerMeMeMeHONH 2HONH 2OglycineΔG transfer kcal/mol MeHOONH 2MeMeMeHONH 2HONH 2OOalaninevalineleucineisoleucine-1.3 (-0.73)-1.9 (-1.69)-1.9 (-2.42)-1.9 (-2.97)( ) side chaincontribution movingfrom water to ethanolOincreasing methyls, decreasing ΔGdesolvationMeMeMeMeMeMeMeMeMe ΔΔG transfer of C-H to C-CH3 0.8 kcal/mol theoretical 3.5 fold boost in potency from methylationAndrews, P. R.; Craik, D. J.; Martin, J. L. J. Med. Chem. 1984, 27, 1648-1657.Nemethy, G. Angew. Chem. Int. Ed. 1967, 6, 195-206.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect The bigger picture of methylation and potency improvements methylation just as likely to decrease binding affinity as it is to increase rare for addition of Me group to give free energy gain greater than 3 kcal/mol (4 cases,0.0019% 10 fold boost (1.36 kcal/mol) - 8% 100 fold boost (2.7 kcal/mol) - 0.4%Leung, C. S.; Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. J. Med. Chem. 2012, 55, 4489-4500.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect The bigger picture of methylation and potency improvements methylation just as likely to decrease binding affinity as it is to increaseMethylEffectfree energyfromthan 3 kcal/mol (4 cases, rare for addition of MeMagicgroupto givefree- energygaingaingreaterMe addition is or above what is predicted0.0019% 10 fold boost (1.36 kcal/mol) - 8% 100 fold boost (2.7 kcal/mol) - 0.4%Leung, C. S.; Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. J. Med. Chem. 2012, 55, 4489-4500.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect How do you invoke the Magic Methyl Effect?a combination of.SolubilityConformationBinding InteractionsMetabolism
Demystifying the Magic Methyl Effect How do you invoke the Magic Methyl Effect?a combination of.SolubilityConformationBinding InteractionsMetabolism
Demystifying the Magic Methyl Effect Conformational preorganization leads to 200-fold boostOONHRNHONHplanarfree rotationONHbiphenyl amide inhibitors of p38α kinaseRK i (nM)IC 50H 2500 16,000Me1275Cl25160F4602900OMe5203300ONHMerotation out of planeONH(inhibitor constant, nM needed toachieve 1/2 max inhibition)Leung, C. S.; Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. J. Med. Chem. 2012, 55, 4489-4500.Angell, R. et al. Bioorg. Med. Chem. Lett. 2008, 18 , 4428-4432.
Demystifying the Magic Methyl Effect Conformational preorganization leads to 200-fold boost methyl in lipophilic pocket - larger groups do not fit several hydrophobic interactions with biphenyl dihedral angle of o-Me-biphenyl free drug matches the bound conformer bestLeung, C. S.; Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. J. Med. Chem. 2012, 55, 4489-4500.Angell, R. et al. Bioorg. Med. Chem. Lett. 2008, 18 , 4428-4432.
Demystifying the Magic Methyl Effect Conformational preorganization leads to 200-fold boost methyl in lipophilic pocket - larger groups do not fit several hydrophobic interactions with biphenyl dihedral angle of o-Me-biphenyl free drug matches the bound conformer bestLeung, C. S.; Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. J. Med. Chem. 2012, 55, 4489-4500.Angell, R. et al. Bioorg. Med. Chem. Lett. 2008, 18 , 4428-4432.
Demystifying the Magic Methyl Effect Conformational preorganization leads to 480-fold shape confirmed by NMR,minimize 1,3-diaxial strainNON96 nMunder development at Merck for insomina,dual antagonist of orexin-1 and -2 receptorsMe0.2 nM"In terms of value, a methyl group that leads to a profound improvement in potency is hard to beat."If α-substituent isFCF3larger alkyl groupsunstable next to heteroatom, not as much steric influence, change in stereoelectronicsrisk of violating Lipinski's rules: CF3: ΔMW 68 g/mol, ΔclogP 0.9,Me: ΔMW 14 g/mol, ΔclogP 0.5)too lipophilic, not a good track record of becoming drugsSchonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect Use of methyl group to decrease binding affinityOHNHOClClHNOTyr355diclofenacK i (µM) COX-1 0.01K i (µM) COX-2 0.01NHNHArg120NH 2OONSAIDOONHNHOHClClSer353Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect Use of methyl group to decrease binding affinityOHNHOClClHNOTyr355diclofenacK i (µM) COX-1 0.01K i (µM) COX-2 0.01H 2NHNHArg120NH 2Ono xibK i (µM) COX-1 3.2K i (µM) COX-2 0.06NSAID, but taken off marketdue to liver damageBarreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect Methyl group installation around freely rotating bonds"rationally developed" combichem-HTS drug discovery tacticHNNMe Patients live up to 5 years longerNHNNO very minimal side effects Bcr-Abl kinase responsible forcell growth of cancer cellsNMe first tyrosine-kinase inhibitor on marketNimatinib - Novartistreats chronic myelogenous leukemiaby inhibiting Bcr-Abl kinaseCapdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nature Rev. Drug Discovery 2002, 1 , 493.Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect Methyl group installation around freely rotating bondsHNNHNNArHNNOmethylationNHNNMeArONPKA, TK and Bcr-Ablk inhibitorHTS to get scaffoldBcr-Ablk selectivity over PKCConformers:NHNHNNMeNArHNNOMeNsteric clashNHNOArconfirmed by X-ray diffractionCapdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nature Rev. Drug Discovery 2002, 1 , 493.Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect A change in conformation isn't adrylBenadrylantihistamines tend to be rigidMe3.7-fold increase in activity2.5-fold decrease in anticholine activityMeNMeOrphenadrineMeMeMeONMerotation out of planeONMeMe5-fold reduction in activity2.1-fold increase in anticholine activityBazzini, P.; Wermuth, C. G. In The Practice of Medicinal Chemistry; Academic Press: San Diego, 2008; pp 431-418.Harms, A. F.; Nauta, W. Th. J. Med. Chem. 1959, 2, 57-77.
Demystifying the Magic Methyl Effect A change in conformation isn't adrylBenadrylantihistamines tend to be rigidMe3.7-fold increase in activity2.5-fold decrease in anticholine activityMeNMeOrphenadrineMeMeMeONMerotation out of planeONMeMe5-fold reduction in activity2.1-fold increase in anticholine activityBazzini, P.; Wermuth, C. G. In The Practice of Medicinal Chemistry; Academic Press: San Diego, 2008; pp 431-418.Harms, A. F.; Nauta, W. Th. J. Med. Chem. 1959, 2, 57-77.
Demystifying the Magic Methyl Effect Overview of where to place Me groups for most impactortho substitutionMeOon substituted alkyl eMe97-fold boostMeClMeONHOHN1333-fold boostNaround two freely rotatable bonds2135-fold boostMeMeMeNNNOMeONClClMeMe159-fold boost598-fold boost480-fold boostSchonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect How do you invoke the Magic Methyl Effect?a combination of.SolubilityConformationBinding InteractionsMetabolism
Demystifying the Magic Methyl Effect Prevention and enhancement of drug metabolismMethyl Groups as Protecting groupProtection of adjacent functional group:HOOprevention of hydrolysisMeMeMeH 2NMeHNOOOplasmatic amidasescleavage imvastatinOHSOONOmeloxicamNNHMethyl Groups as a Metabolic Soft SpotChange in half-life:MeSMeMeheterocycle susceptibleto oxidationRRMeBarreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect Prevention and enhancement of drug metabolismOHSOONNNHOH[O]OSCYP2C9SMeOONSNHOHONH 2MeSOOsudoxicamNSNHNMeMeOmeloxicam Mechanism of metabolization of thiazole derivativesR1NRSR1[O]NROShydrolysisNH 2RSOR1OH Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect Prevention and enhancement of drug metabolismOHSOONNOH[O]OSNHCYP2C9SMeOONSNHOHONNH 2MeSOOsudoxicamNMeSNHMeOmeloxicam Alternative , E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect Oxidation of benzylic methyl groupsMeFNCF3methylation to decreasehalf-lifeNNH 2NO 2SCF3NMeO 2Slong half-life leads to accumulationof drug and possible side effectscelecoxibanti-inflammatory drugOHOHO[O]NMeO 2SCF3NNCF3NMeO 2SBarreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect Prodrug exampleOHSO2Nincrease ihelmintic drugin vivoSMeONHSMe[P]ONMeMeONHNMemore lipophilic,better bioavailabilityBarreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect How are methyl groups typically installed?HNDe Novo SynthesisONNHOSNONMeMeMeGSK221087540 nM, 754-fold boostSuzuki nsformationstransformationsAACallOHNNSNH ORµWaveRXselective reductionSNNNORRPilla, M. et al. Bioorg. Med. Chem. Lett. 2010, 20, 7521-7524.
Demystifying the Magic Methyl Effect How are methyl groups typically installed?AA CallCall forfor C-HC-H toto C-MeC-Me transformationstransformationsi) Boc 2Oii) RuO 2, NaIO 4iii) MeMgBrMeMeNHNHiv) TFA then NaOHv) Pd(OH) 2/C, H 2Me41% Direct methylation will come in handy during fine-tuning stages of drug development Many cases where methylation of advanced intermediate only possible via de novo Payoff is unknown Need to explore methylated chemical space Recent advances made for CF3, CHF2, monofluorination - leaving Me behindCui, L.; Peng, Y.; Zhang, L. J. Am. Chem. Soc. 2009, 131 , 8394-8395.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect Modes of Actiona combination of.SolubilityConformationBinding InteractionsMetabolismlater.Current Synthetic Methods
Demystifying the Magic Methyl Effect Methylation of C(sp2)-H Bonds Most acidic C-H via induction or ortho-directionDirect deprotonation via inductive effects:OMOMtBuLi, THFOMOMOMOMMeILiMe-78 CLimitations: need base stable functional groupsLi-halogen exchange requires de novo synthesis directed C-H activation with transition metalFirst report of complementary acidic methodology:MeOMeNH1.5 equiv Pd(OAc) 2AcOH, 10 equiv MeI, 60 CHNOOPdIIL nMeIMeNHMevia PdIV81% yldSnieckus, V. Chem. Rev. 1990, 90, 879-933.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.Tremont, S. J.; Rahman, H. U. J. Am Chem. Soc. 1984, 106 , 5759-5760.
Demystifying the Magic Methyl Effect Methylation of C(sp2)-H Bonds Improvements with Pd(OAc) 2 and MeIcatalytic Pd(OAc) 2:OMeOO3 equiv MeI, 5 mol% Pd(OAc) 2NHNMeOO2, NaOTf, K 2CO3tAmOH, 125 C, 36 hrNHNMe90%Ambient temperatures:MeOHNMeO2 equiv MeI, 5 mol% Pd(OAc) 2HNMeOAgOAc, Cu(OTf)2TFA, CH2Cl2, 25 C, 11 hrMeMeO86%Jang, M. J.; Youn, S. W. Bull. Korean Chem. Soc. 2011, 32, 2865-2866.Zhao, Z.; Chen, G. Org. Lett. 2011, 13 , 4850-4853.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect Methylation of C(sp2)-H Bonds Transmetalation reagents can be usedvarious oxidants needed for metal 4OH83%MeBF 3KMeB(OH) 210 mol% Pd(OAc) 2,BQ, Cu(OAc)2MeCN, 100 C, 40 h10 mol% Pd(OAc) 2,MnF 3, AcOHTFE/H2O, 40 C, 3h10 mol% Pd(OAc) 2,air, BQ, AgOActAMOH, 100 C, 20 hOHNMeMeMeMgClMeN10 mol% Co(acac)2DMPU, THF, rt, 12 hMe68%Me76%MeCOOH2.5 mol% [{Rh(CO)2Cl}2],Boc 2O, toluene,140 C, 24 hrSchonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect Methylation of C(sp2)-H Bonds Transmetalation reagents can be usedvarious oxidants needed for metal e4MeBF 3K10 mol% Pd(OAc) 2,MnF 3, AcOHTFE/H2O, 40 C, 3h10 mol% Pd(OAc) 2,air, BQ, AgOActAMOH, 100 C, 20 hOMePhOOHNMe MeMePh10 mol% Co(acac)2 Me MeDMPU, THF, rt, 12 hperoxides as transmetallatingreagents68%Me83%MeB(OH) 210 mol% Pd(OAc) 2,BQ, Cu(OAc)2MeCN, 100 C, 40 hMeMgClO10Memol% Pd(OAc)N2,neat,140 C, 12 hMeβ-methyl elimination76%MeCOOHN2.5 mol% [{Rh(CO)54% 2Cl}2],MeBoc 2O, toluene,140 C, 24 hrSchonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect Methylation of C(sp2)-H Bonds Application of Minisci reactionEtON NEtCHOFeSO 4 7H 2OH 2O2, H 2SO 4ONNOOEtOH77%OEtOHOeasy installation of Me for SAR:NMeNONOONOvia AcOHEtEtOHOIrinotecan-PfizerTopoisomerase I inhibitor,cancer treatmentONNOEtOHOSchonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.Duncton, M. A. J. Med. Chem. Comm. 2011, 2, 1135-1161.
Demystifying the Magic Methyl Effect Methylation of C(sp2)-H Bonds Me radical generation known to functionalize arenesOMeOHOOOMeMeSHOSMeMeOOOMeHOS MeMeFenton's Reagent with DMSOFeSO 4 7H2O, H 2O2, DMSOdiacyl peroxidesheat or hνMeMinisci with Fe 2 Minisci with Ag AgNO2, (NH 4)2S2O8, H 2SO 4FeSO 4 7H2O, tBuO 2H, H 2SO 4tBuO 2H Fe 2 O Fe 3 MeOHcarboxylic acidFe 3 tBuO 2 Ag S2O82-OH-H -CO2 MeMe2 SO 42--H OFe 2 2 Ag2 OHAg2 -CO2Ag Mecarboxylic acidGiordano, C.; Minisci, F.; Tortelli, V.; Vismara, E. J. Chem. Soc., Perkin Trans. 2 1984, 293.Levy, M.; Szwarc, M. J. Am. Chem. Soc. 1955, 77, 1949.
Demystifying the Magic Methyl Effect Methylation of C(sp2)-H Bonds Me radical generation known to functionalize arenesOMeOHOOOMeMeSHOSMeMeOOOMeHOS MeMeFenton's Reagent with DMSOFeSO 4 7H2O, H 2O2, DMSOdi
MacMillan Group Meeting June 11, 2015. Demystifying the Magic Methyl Effect. Demystifying the Magic Methyl Effect "In comparison to its importance to the pharmaceutical industry, the methyl group is, in our opinion, underrepresented in recent synthetic chemistry.
Sesquicocoate, Methyl Glucose Sesquiisostearate, Methyl Glucose Sesquilaurate, Methyl Glucose Sesquioleate, and Methyl Glucose Sesquistearate, is typically achieved via transesterification of an appropriate fatty acid methyl ester (e.g., methyl laurate to get Methyl Glucose Laurate) with methyl glucoside (releasing methanol as a by-product).
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of enterics can be differentiated by the Methyl Red-Voges Proskauer (MR-VP) test. Methyl red is a pH indicator. In the presence of highly acidic conditions, as generated by mixed acid fermenters, the indicator appears read (Fig. 1). As the pH rises, i.e., becomes alkaline, methyl red turns yellow. Hence, the addition of methyl red to a culture .File Size: 275KBPage Count: 5Explore furtherMethyl Red (MR) Test: Principle, Procedure, Results .microbeonline.comMethyl Red / Voges-Proskauer (MR/VP) - University of Wyomingwww.uwyo.eduMethyl Red and Voges Proskauer Test - Principle, Resultmicrobiologynote.comWelcome to Microbugz - Methyl Red & Vogues-Proskauer Testwww.austincc.eduMRVP Results - Western Michigan Universityhomepages.wmich.eduRecommended to you based on what's popular Feedback
3006 AGMA Toilet Additive 1338 (3006) 19.0% 2914 CERAVON BLUE V10 DC (2914) 0.05% 2922 FORMALDEHYDE REODORANT ALTERNATIVE (2922) 0.6% 3 Water (3) 80.05% Constituent Chemicals 1 Water (3) 80.05% CAS number: 7732-18-5 EC number: 231-791-2 Product number: — EU index number: — Physical hazards Not Classified Health hazards Not Classified Environmental hazards Not Classified 2 Bronopol (INN .
