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The mechanism of thalidomide's
teratogenic action has led to over 2000 research papers and the proposal of 15 or 16 plausible mechanisms.[1]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[2] that promote angiogenesis. Surface
integrinαVβ3 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.[3][4] 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.[5][6][7][8][9][10][11] Further investigation into this phenomenon found that at least eight other proteins in the growth-stimulating cascade too had promotors containing this region.[1][12] 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, thereby exerting the tetratogenic effects seen in thalidomide-induced birth defects.[1][12]
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".[13][14]
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.[17]
Thiothalidomides have a greater inhibitory effect on TNF-α than thalidomide.
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[18], 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[19], TNFA, or block
translation of the mRNA.[20] 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[21] in the following order:
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
Thalidomide is synthesized into a
racemic mixture, however separating the mixture into a enatiomerically pure solution would prove fruitless[22][23][24] as the racemization can occur in vivo.[25][26][22][27]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.[28] 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).[28] Celegne Corporation's original method resulted in a 31% yield of S-thalidomide, whereas the two-step synthesis yields 85-93% product that is 99% pure.
Muller et al.'s two-step thalidomide synthesis
From article
Mechanism of action
The precise mechanism of action for thalidomide is unknown, but possible mechanisms include anti-angiogenic and oxidative stress-inducing effects.[29] It also inhibits
TNF-α,
IL-6,
IL-10 and
IL-12 production,[30] modulates the production of
IFN-γ[30] and enhances the production of
IL-2,
IL-4 and
IL-5 by immune cells.[30] It increases lymphocyte count, costimulates T cells and modulates
natural killer cell cytotoxicity.[30] It also inhibits
NF-κB and
COX-2 activity.[29]
The mechanism of thalidomide's
teratogenic action has led to over 2000 research papers and the proposal of 15 or 16 plausible mechanisms.[1]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[2] that promote angiogenesis. Surface
integrinαVβ3 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.[3][4] 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.[5][6][7][8][9][10][11] Further investigation into this phenomenon found that at least eight other proteins in the growth-stimulating cascade too had promotors containing this region.[1][12] 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, thereby exerting the tetratogenic effects seen in thalidomide-induced birth defects. [1][12]
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".[13][14]
The two enantiomers of thalidomide: Left: (S)-(−)-thalidomide Right: (R)-(+)-thalidomide
Thalidomide is
racemic; the individual enantiomers can
racemize due to the acidic hydrogen at the
chiral centre, which is the carbon of the glutarimide ring bonded to the phthalimide substituent. The racemization process can occur in vivo[25][26][22][27] so that any plan to administer a purified single enantiomer to avoid the teratogenic effects will most likely be in vain.[22][23][24]
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.[33]
Thiothalidomides have a greater inhibitory effect on TNF-α than thalidomide.
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[34], 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[35], TNFA, or block
translation of the mRNA.[36] 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[37] in the following order:
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.
Cereblon
Several studies have shown that the mechanism of action for thalidomide involves binding to the protein
cereblon, a ubiquitin ligase substrate adapter protein,[38] which is important in limb formation[39] and the proliferative capacity of myeloma cells. Ubiquitin ligases function by reducing the cellular levels of proteins and thalidomide has been shown to alter the set of proteins which CRBN can degrade.[40] Cereblon's relevance to human congenital defects was confirmed in studies that reduced the production of cereblon in developing chick and zebrafish embryos using genetic techniques. These embryos had defects similar to those treated with thalidomide. Interestingly, mice treated with thalidomide do not display teratogenicity of their offspring as seen in humans.[41]
Thalidomide is synthesized into a
racemic mixture, however separating the mixture into a enatiomerically pure solution would prove fruitless[22][23][24] as the racemization can occur in vivo.[25][26][22][27]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.[28] 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).[28] Celegne Corporation's original method resulted in a 31% yield of S-thalidomide, whereas the two-step synthesis yields 85-93% product that is 99% pure.
^
abStephens, 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)
^
abNeubert, 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. {{
cite journal}}: |access-date= requires |url= (
help)
^
abPasumarthi, 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.
^
abBoisclair, 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)
^
abPerez-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)
^
abWerner, 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.
^
abCooke, David W.; Bankert, Laura A.; Roberts, Charles T.; LeRoith, Derek; Casella, Samuel J. (June 1991). "Analysis of the human type I insulin-like growth factor receptor promoter region". Biochemical and Biophysical Research Communications. 177 (3): 1113–1120.
doi:
10.1016/0006-291X(91)90654-P.
^
abAdamo, M; Roberts CT, Jr; LeRoith, D (January 1992). "How distinct are the insulin and insulin-like growth factor I signalling systems?". BioFactors (Oxford, England). 3 (3): 151–7.
PMID1599609.
^
abMyers 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.
PMID7961833.
^
abTherapontos, C; Erskine, L; Gardner, ER; Figg, WD; Vargesson, N (26 May 2009). "Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation". Proceedings of the National Academy of Sciences of the United States of America. 106 (21): 8573–8.
PMID19433787.
^
abVargesson, N (June 2015). "Thalidomide-induced teratogenesis: history and mechanisms". Birth defects research. Part C, Embryo today : reviews. 105 (2): 140–56.
PMID26043938.
^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.
PMID20692646.
^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.
PMID11239407.
^
abcdefMuller GW, Corral LG, Shire MG, Wang H, Moreira A, Kaplan G, Stirling DI (August 1996). "Structural modifications of thalidomide produce analogs with enhanced tumor necrosis factor inhibitory activity". J. Med. Chem. 39 (17): 3238–40.
doi:
10.1021/jm9603328.
PMID8765505.
^
abcBartlett JB, Dredge K, Dalgleish AG (April 2004). "The evolution of thalidomide and its IMiD derivatives as anticancer agents". Nat. Rev. Cancer. 4 (4): 314–22.
doi:
10.1038/nrc1323.
PMID15057291.
^
abcMan HW, Schafer P, Wong LM, Patterson RT, Corral LG, Raymon H, Blease K, Leisten J, Shirley MA, Tang Y, Babusis DM, Chen R, Stirling D, Muller GW (March 2009). "Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor". J. Med. Chem. 52 (6): 1522–4.
doi:
10.1021/jm900210d.
PMID19256507.
^
abcCite error: The named reference clinp was invoked but never defined (see the
help page).
^
abcEriksson T, Björkman S, Roth B, Fyge A, Höglund P (1995). "Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide". Chirality. 7 (1): 44–52.
doi:
10.1002/chir.530070109.
PMID7702998.
^
abKim, 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.
PMID21507989.
^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.
PMID20692646.
^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.
PMID11239407.
^
abHashimoto, Y.; Tanatani, A.; Nagasawa, K.; Miyachi, H. (2004). "Thalidomide as a multitarget drug and its application as a template for drug design". Drugs of the Future. 29 (4): 383.
doi:
10.1358/dof.2004.029.04.792298.
ISSN0377-8282.
^
abLiu, Bo; Su, Lei; Geng, Jingkun; Liu, Junjie; Zhao, Guisen (2010). "Developments in Nonsteroidal Antiandrogens Targeting the Androgen Receptor". ChemMedChem. 5 (10): 1651–1661.
doi:
10.1002/cmdc.201000259.
ISSN1860-7179.
^
abHashimoto, Yuichi (2003). "Structural development of synthetic retinoids and thalidomide-related molecules". Cancer Chemotherapy and Pharmacology. 52 (0): 16–23.
doi:
10.1007/s00280-003-0590-3.
ISSN0344-5704.
^Nuttall, Frank Q.; Warrier, Rohit S.; Gannon, Mary C. (2015). "Gynecomastia and drugs: a critical evaluation of the literature". European Journal of Clinical Pharmacology. 71 (5): 569–578.
doi:
10.1007/s00228-015-1835-x.
ISSN0031-6970.