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Mechanism of action

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The precise mechanism of action for thalidomide is unknown, but possible mechanisms include anti-angiogenic and oxidative stress-inducing effects.[1] It also inhibits TNF-α, IL-6, IL-10 and IL-12 production,[2] modulates the production of IFN-γ[2] and enhances the production of IL-2, IL-4 and IL-5 by immune cells.[2] It increases lymphocyte count, costimulates T cells and modulates natural killer cell cytotoxicity.[2] It also inhibits NF-κB and COX-2 activity.[1]

The mechanism of thalidomide's teratogenic action has led to over 2000 research papers and the proposal of 15 or 16 plausible mechanisms.[3] Angiogenesis is critical during limb development of the foetus. In 1998, it was found in vivo that during limb development thalidomide was able to inhibit the stimulatory effects of growth factors FGF-2 and IGF-1[4] that promote angiogenesis. Surface integrin αVβ3 is notably important in this process Previous work showed thalidomide's ability to decrease integrin production on the cell surface, decreasing the cell's ability to stimulate new blood vessels, and inhibit angiogenesis stimulated by FGF-2.[5]Cite error: There are <ref> tags on this page without content in them (see the help page).[6] It was soon found that αVβ3 had several GC box sequences in its promoter region and the same was true for FGF-2 and IGF-1 and their receptors on the cell surface.[7][8][9][10]Cite error: A <ref> tag is missing the closing </ref> (see the help page).[11] Further investigation into this phenomenon found that at least eight other proteins in the growth-stimulating cascade too had promotors containing this region.[12][13] Thalidomide has a high affinity for guanine, thus it was hypothesized that Thalidomide intercalates into these GC boxes and prevents integrins from stimulating new blood vessels that support limb development. [12][13]

In 2009, research by other groups confirmed "conclusively that loss of newly formed blood vessels is the primary cause of thalidomide teratogenesis, and developing limbs are particularly susceptible because of their relatively immature, highly angiogenic vessel network".[14][15]

TNF-α

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Tumor necrosis factor alpha (TNF-α) is a cytokine that is chiefly involved in regulating white blood cells. Changes in the regulation of this protein has been found to be related to various diseases such as Alzheimer's disease[16] and cancer.[17].

In 1990, a group of researchers in Brazil noted that TNF-α levels went up in leprosy reactional states and observed that TNF levels decreased in some patients on treatment with thalidomide, hence potentially explaining the efficacy of thalidomide in treating ENL.[18]

 
Thiothalidomides have a greater inhibitory effect on TNF-α than thalidomide. The more substituted the molecule, the stronger its inhibitory effect.

In light of this, further study of how this drug affected TNF-α were conducted. In 1993, thalidomide was found to selectively degrade TNF-α mRNA[19], however how it does so is unclear. This is compared to other known TFN-α inhibitors, some of which have been found to block transcription of the TNF-α gene[20], TNFA, or block translation of the mRNA.[21] Further, this reduction in TNF-α lead to a decrease in inflammatory cytokine levels, suggesting thalidomide's use in treating other inflammatory infections.

Thalidomide analogs have been found to have even more profound effects on TNF-α inhibition than their parent molecule. Replacing thalidomide's carbonyls with thiones increased its ability to inhibit TNF-α[22] in the following order:

trithiothalidomide > dithiothalidomide > monothiothalidomide > thalidomide

as seen in the structures to the right. It is hypothesized that this these analogs act on the 3'-UTR of TNFA to exert their effects.

Synthesis

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Thalidomide is synthesized into a racemic mixture, however separating the mixture into a enatiomerically pure solution would prove fruitless[23][24][25] as the racemization can occur in vivo.[26][27][23][28] Celgene Corporation originally synthesized thalidomide using a three-step sequence starting with L-glutamic acid treatment, but this has since been reformed by the use of L-glutamine.[29] As shown in the image below, N-carbethoxyphtalimide (1) can react with L-glutamine to yield N-Phthaloyl-L-glutamine (2). Cyclization of N-Phthaloyl-L-glutamine occurs using carbonyldiimidazole, which then yields thalidomide (3).[29] This method of synthesis allows for a high yield of thalidomide, which is useful for industrial purposes.

 
Muller et al.'s two-step thalidomide synthesis
  1. ^ a b Kim, James H.; Scialli, Anthony R. (2011). "Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease". Toxicological Sciences. 122 (1): 1–6. doi:10.1093/toxsci/kfr088. PMID 21507989.
  2. ^ a b c d Singhal S, Mehta J (February 2002). "Thalidomide in cancer". Biomedicine & Pharmacotherapy. 56 (1): 4–12. doi:10.1016/S0753-3322(01)00146-9. PMID 11905508.
  3. ^ Stephens TD, Bunde CJ, Fillmore BJ (June 2000). "Mechanism of action in thalidomide teratogenesis". Biochem. Pharmacol. 59 (12): 1489–99. doi:10.1016/S0006-2952(99)00388-3. PMID 10799645.
  4. ^ Stephens, T; Bunde, C; Torres, R; Hackett, D; Stark, M; Smith, D; Fillmore, B (1998). "Thalidomide inhibits limb development through its antagonism of IGF-1+ FGF-2+ heparin". Tertology. 57 (112). {{cite journal}}: |access-date= requires |url= (help)
  5. ^ Neubert, R; Hinz, N; Thiel, R; Neubert, D (15 Dec 1995). "Down-regulation of adhesion receptors on cells of primate embryos as a probable mechanism of the teratogenic action of thalidomide". Life sciences. 58 (4): 295–316. doi:0024-3205(95)02290-2. {{cite journal}}: |access-date= requires |url= (help); Check |doi= value (help)
  6. ^ D'Amato RJ, Loughnan MS, Flynn E, Folkman J (1994). "Thalidomide is an inhibitor of angiogenesis". Proceedings of the National Academy of Sciences of the United States of America. 91 (9): 4082–4085. Bibcode:1994PNAS...91.4082D. doi:10.1073/pnas.91.9.4082. PMC 43727. PMID 7513432.
  7. ^ Pasumarthi, Kishore B. S.; Jin, Yan; Cattini, Peter A. (18 November 2002). "Cloning of the Rat Fibroblast Growth Factor-2 Promoter Region and Its Response to Mitogenic Stimuli in Glioma C6 Cells". Journal of Neurochemistry. 68 (3): 898–908. doi:10.1046/j.1471-4159.1997.68030898.x.
  8. ^ Boisclair, Yves R.; Brown, Alexandra L.; Casola, Stefano; Rechler, Matthew M (25 Nov 1993). "Three Clustered Spl Sites Are Required for Efficient Transcription of the TATA-less Promoter of the Gene for Insulin-like Growth Factor-binding Protein-2 from the Rat". The Journal of Biological Chemistry. 268 (33): 24892–24901. {{cite journal}}: |access-date= requires |url= (help)
  9. ^ Perez-Castro, Ana V.; Wilson, Julie; Altherr, Michael R. (April 1997). "Genomic Organization of the Human Fibroblast Growth Factor Receptor 3 (FGFR3) Gene and Comparative Sequence Analysis with the MouseFgfr3Gene". Genomics. 41 (1): 10–16. doi:10.1006/geno.1997.4616. {{cite journal}}: |access-date= requires |url= (help)
  10. ^ Werner, Haim; Stannard, Bethel; Bach, Mark A.; LeRoith, Derek; Roberts, Charles T. (June 1990). "Cloning and characterization of the proximal promoter region of the rat insulin-like growth factor I (IGF-I) receptor gene". Biochemical and Biophysical Research Communications. 169 (3): 1021–1027. doi:10.1016/0006-291X(90)91996-6.
  11. ^ Myers MG, Jr; Grammer, TC; Wang, LM; Sun, XJ; Pierce, JH; Blenis, J; White, MF (18 November 1994). "Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation". The Journal of biological chemistry. 269 (46): 28783–9. PMID 7961833.
  12. ^ a b Stephens, TD; Bunde, CJ; Fillmore, BJ (15 June 2000). "Mechanism of action in thalidomide teratogenesis". Biochemical pharmacology. 59 (12): 1489–99. PMID 10799645.
  13. ^ a b Stephens, TD; Fillmore, BJ (March 2000). "Hypothesis: thalidomide embryopathy-proposed mechanism of action". Teratology. 61 (3): 189–95. PMID 10661908.
  14. ^ Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N (May 2009). "Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation". Proc. Natl. Acad. Sci. U.S.A. 106 (21): 8573–8. Bibcode:2009PNAS..106.8573T. doi:10.1073/pnas.0901505106. JSTOR 40482723. PMC 2688998. PMID 19433787.
  15. ^ Vargesson N (2015). "Thalidomide-induced teratogenesis: history and mechanisms". Birth Defects Res. C Embryo Today. 105 (2): 140–56. doi:10.1002/bdrc.21096. PMC 4737249. PMID 26043938.
  16. ^ Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010). "A meta-analysis of cytokines in Alzheimer's disease". Biol Psychiatry. 68 (10): 930–941. doi:10.1016/j.biopsych.2010.06.012. PMID 20692646.
  17. ^ Locksley RM, Killeen N, Lenardo MJ (2001). "The TNF and TNF receptor superfamilies: integrating mammalian biology". Cell. 104 (4): 487–501. doi:10.1016/S0092-8674(01)00237-9. PMID 11239407.
  18. ^ Sarno EN, Grau GE, Vieira LM, Nery JA (April 1991). "Serum levels of tumour necrosis factor-alpha and interleukin-1 beta during leprosy reactional states". Clin. Exp. Immunol. 84 (1): 103–8. doi:10.1111/j.1365-2249.1991.tb08131.x. PMC 1535359. PMID 2015700.
  19. ^ Moriera, Andre; Sampaio, Elizabeth; Antonina, Zmuidzinas; Paula, Frindt; Smith, Kendall; Kaplan, Gilla (1 June 1993). "Thalidomide Exerts Its Inhibitory Action on Tumor Necrosis Factor α by Enhancing mRNA Degradation". The Journal of Experimental Medicine. 177 (6): 1675–1680. doi:10.1084/jem.177.6.1675. {{cite journal}}: |access-date= requires |url= (help)
  20. ^ Doherty, G; Jensen, J; Alexander, H; Buresh, C; Norton, J (1 Aug 1991). "Pentoxifylline suppression of tumor necrosis factor gene transcription". Surgery. 110 (2): 192–198. {{cite journal}}: |access-date= requires |url= (help)
  21. ^ Han, J; Thompson, P; Beutler, B (1 Jul 1990). "Dexamethosone and penthoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway". The Journal of Experimental Medicine. 172 (1): 391–394. {{cite journal}}: |access-date= requires |url= (help)
  22. ^ Greig, Nigel; Girodano, Tony; Zhu, Xiaoxiang; Yu, Qian-sheng; Perry, Tracy; Holloway, Harold; Brossi, Arnold; Rogers, Jack; Sambamurti, Kumar; Lahiri, Debomoy (2004). "Thalidomide-based TNF-α inhibitors for neurodegenerative diseases". Acta neurobiologiae experimentalis. 64 (1): 1–9. {{cite journal}}: |access-date= requires |url= (help)
  23. ^ a b Cite error: The named reference Muller_1996 was invoked but never defined (see the help page).
  24. ^ Cite error: The named reference Bartlett2004 was invoked but never defined (see the help page).
  25. ^ Cite error: The named reference pmid19256507 was invoked but never defined (see the help page).
  26. ^ Cite error: The named reference clinp was invoked but never defined (see the help page).
  27. ^ Cite error: The named reference stereospecific44 was invoked but never defined (see the help page).
  28. ^ Cite error: The named reference pmid14505639 was invoked but never defined (see the help page).
  29. ^ a b Muller, George; Konnecke, William; Smith, Alison; Khetani, Vikram (19 March 1999). "A Concise Two-Step Synthesis of Thalidomide". Organic Process Research & Development. 3 (2): 139–140. doi:10.1021/op980201b. Retrieved 23 April 2017.
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