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Monomethyl Auristatin F Synthesis Essay

Names
IUPAC name
(S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid
Identifiers
AbbreviationsMMAF
ChemSpider
  • InChI=1S/C39H65N5O8/c1-12-25(6)34(43(9)38(48)33(24(4)5)42-37(47)32(40-8)23(2)3)30(51-10)22-31(45)44-20-16-19-29(44)35(52-11)26(7)36(46)41-28(39(49)50)21-27-17-14-13-15-18-27/h13-15,17-18,23-26,28-30,32-35,40H,12,16,19-22H2,1-11H3,(H,41,46)(H,42,47)(H,49,50)/t25-,26+,28-,29-,30+,32-,33-,34-,35+/m0/s1
    Key: MFRNYXJJRJQHNW-DEMKXPNLSA-N
  • InChI=1/C39H65N5O8/c1-12-25(6)34(43(9)38(48)33(24(4)5)42-37(47)32(40-8)23(2)3)30(51-10)22-31(45)44-20-16-19-29(44)35(52-11)26(7)36(46)41-28(39(49)50)21-27-17-14-13-15-18-27/h13-15,17-18,23-26,28-30,32-35,40H,12,16,19-22H2,1-11H3,(H,41,46)(H,42,47)(H,49,50)/t25-,26+,28-,29-,30+,32-,33-,34-,35+/m0/s1
    Key: MFRNYXJJRJQHNW-DEMKXPNLBL
  • O=C(N2[C@H]([C@H](OC)[C@H](C(=O)N[C@H](C(=O)O)Cc1ccccc1)C)CCC2)C[C@@H](OC)[C@@H](N(C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C)C)[C@@H](C)CC
Properties
C39H65N5O8
Molar mass731.98 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Monomethyl auristatin F (MMAF) is a synthetic antineoplastic agent.[1] It is part of some experimental anti-cancer antibody-drug conjugates such as vorsetuzumab mafodotin and SGN-CD19A. In International Nonproprietary Names for MMAF-antibody-conjugates, the name mafodotin refers to MMAF plus its attachment structure to the antibody.[2]

Mechanism of action[edit]

Monomethyl auristatin F is an antimitotic agent which inhibits cell division by blocking the polymerisation of tubulin. It is linked to an antibody with high affinity to structures on cancer cells, causing MMAF to accumulate in such cells.[3]

Chemistry[edit]

MMAF is actually desmethyl-auristatin F; that is, the N-terminal amino group has only one methyl substituent instead of two as in auristatin F itself.[3]

See also[edit]

References[edit]

  1. ^Tai, Y. T.; Mayes, P. A.; Acharya, C; Zhong, M. Y.; Cea, M; Cagnetta, A; Craigen, J; Yates, J; Gliddon, L; Fieles, W; Hoang, B; Tunstead, J; Christie, A. L.; Kung, A. L.; Richardson, P; Munshi, N. C.; Anderson, K. C. (2014). "Novel afucosylated anti-B cell maturation antigen-monomethyl auristatin F antibody-drug conjugate (GSK2857916) induces potent and selective anti-multiple myeloma activity". Blood. 123 (20): 3128–38. doi:10.1182/blood-2013-10-535088. PMID 24569262. 
  2. ^Statement on a nonproprietary name adopted by the USAN Council: Mafodotin
  3. ^ abcDosio, F.; Brusa, P.; Cattel, L. (2011). "Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components". Toxins. 3 (12): 848. doi:10.3390/toxins3070848. 

1. Wu AM, Senter PD. Arming antibodies: Prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137–1146.[PubMed]

2. Polakis P. Arming antibodies for cancer therapy. Curr Opin Pharmacol. 2005;5:382–387.[PubMed]

3. Lambert JM. Drug-conjugated monoclonal antibodies for the treatment of cancer. Curr Opin Pharmacol. 2005;5:543–549.[PubMed]

4. Vater CA, Goldmacher VS. Antibody-cytotoxic compound conjugates for oncology. Macromolecular Anticancer Therapeutics. 2010 Part 4:331–369.

5. Kovtun YV, Goldmacher VS. Cell killing by antibody-drug conjugates. Cancer Lett. 2007;255:232–240.[PubMed]

6. Okeley NM, et al. Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin Cancer Res. 2010;16:888–897.[PubMed]

7. Hamann PR, et al. Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem. 2002;13:47–58.[PubMed]

8. Beck A, et al. The next generation of antibody-drug conjugates comes of age. Discov Med. 2010;10:329–339.[PubMed]

9. Francisco JA, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102:1458–1465.[PubMed]

10. Doronina SO, et al. Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: Effects of linker technology on efficacy and toxicity. Bioconjug Chem. 2006;17:114–124.[PubMed]

11. Lewis Phillips GD, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280–9290.[PubMed]

12. Tolcher AW, et al. Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: A phase I, pharmacokinetic, and biologic correlative study. J Clin Oncol. 2003;21:211–222.[PubMed]

13. Goff LW, et al. A phase II study of IMGN242 (huC242-DM4) in patients with CanAg-positive gastric or gastroesophageal (GE) junction cancer. J Clin Oncol. 2009;27 e15625.

14. DiJoseph JF, et al. Antibody-targeted chemotherapy with CMC-544: A CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood. 2004;103:1807–1814.[PubMed]

15. Tse KF, et al. CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma. Clin Cancer Res. 2006;12:1373–1382.[PubMed]

16. Hamblett KJ, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10:7063–7070.[PubMed]

17. Wang L, Amphlett G, Blättler WA, Lambert JM, Zhang W. Structural characterization of the maytansinoid-monoclonal antibody immunoconjugate, huN901-DM1, by mass spectrometry. Protein Sci. 2005;14:2436–2446.[PMC free article][PubMed]

18. Junutula JR, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925–932.[PubMed]

19. Junutula JR, et al. Engineered thio-trastuzumab-DM1 conjugate with an improved therapeutic index to target human epidermal growth factor receptor 2-positive breast cancer. Clin Cancer Res. 2010;16:4769–4778.[PubMed]

20. Shen B-Q, et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol. 2012;30:184–189.[PubMed]

21. Wang L, Brock A, Herberich B, Schultz PG. Expanding the genetic code of Escherichia coli. Science. 2001;292:498–500.[PubMed]

22. Wang L, Zhang Z, Brock A, Schultz PG. Addition of the keto functional group to the genetic code of Escherichia coli. Proc Natl Acad Sci USA. 2003;100:56–61.[PMC free article][PubMed]

23. Young TS, Ahmad I, Yin JA, Schultz PG. An enhanced system for unnatural amino acid mutagenesis in E. coli. J Mol Biol. 2010;395:361–374.[PubMed]

24. Liu W, Brock A, Chen S, Chen S, Schultz PG. Genetic incorporation of unnatural amino acids into proteins in mammalian cells. Nat Methods. 2007;4:239–244.[PubMed]

25. Hutchins BM, et al. Site-specific coupling and sterically controlled formation of multimeric antibody fab fragments with unnatural amino acids. J Mol Biol. 2011;406:595–603.[PMC free article][PubMed]

26. Hutchins BM, et al. Selective formation of covalent protein heterodimers with an unnatural amino acid. Chem Biol. 2011;18:299–303.[PMC free article][PubMed]

27. Dirksen A, Hackeng TM, Dawson PE. Nucleophilic catalysis of oxime ligation. Angew Chem Int Ed Engl. 2006;45:7581–7584.[PubMed]

28. Ross JS, et al. The HER-2 receptor and breast cancer: Ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009;14:320–368.[PubMed]

29. Krop IE, et al. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol. 2010;28:2698–2704.[PubMed]

30. Doronina SO, et al. Novel peptide linkers for highly potent antibody-auristatin conjugate. Bioconjug Chem. 2008;19:1960–1963.[PubMed]

31. Oflazoglu E, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171–6180.[PubMed]

32. Zhao RY, et al. Synthesis and evaluation of hydrophilic linkers for antibody-maytansinoid conjugates. J Med Chem. 2011;54:3606–3623.[PubMed]

33. Jones DS, et al. Synthesis of LJP 993, a multivalent conjugate of the N-terminal domain of β2GPI and suppression of an anti-β2GPI immune response. Bioconjug Chem. 2001;12:1012–1020.[PubMed]

34. Chambers AF. MDA-MB-435 and M14 cell lines: Identical but not M14 melanoma? Cancer Res. 2009;69:5292–5293.[PubMed]

35. Hollestelle A, Schutte M. Comment Re: MDA-MB-435 and M14 cell lines: Identical but not M14 Melanoma? Cancer Res. 2009;69:7893–7893.[PubMed]

36. Prat A, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010;12:R68.[PMC free article][PubMed]

37. Kazane SA, et al. Site-specific DNA-antibody conjugates for specific and sensitive immuno-PCR. Proc Natl Acad Sci USA. 2012;109:3731–3736.[PMC free article][PubMed]

38. Alley SC, et al. The pharmacologic basis for antibody-auristatin conjugate activity. J Pharmacol Exp Ther. 2009;330:932–938.[PubMed]

39. Boswell CA, et al. Impact of drug conjugation on pharmacokinetics and tissue distribution of anti-STEAP1 antibody-drug conjugates in rats. Bioconjug Chem. 2011;22:1994–2004.[PubMed]

40. Gross S, Piwnica-Worms D. Spying on cancer: Molecular imaging in vivo with genetically encoded reporters. Cancer Cell. 2005;7:5–15.[PubMed]

41. Klerk CPW, et al. Validity of bioluminescence measurements for noninvasive in vivo imaging of tumor load in small animals. Biotechniques. 2007;43(1, Suppl):7–13, 30.[PubMed]

42. O’Neill K, Lyons SK, Gallagher WM, Curran KM, Byrne AT. Bioluminescent imaging: A critical tool in pre-clinical oncology research. J Pathol. 2010;220:317–327.[PubMed]

43. Staflin K, et al. Targeting activated integrin alphavbeta3 with patient-derived antibodies impacts late-stage multiorgan metastasis. Clin Exp Metastasis. 2010;27:217–231.[PMC free article][PubMed]

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