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Signum Biosciences

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Signum Biosciences
Names
IUPAC name 4-(((1R)-1-carboxy-2-(((2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecen-1-yl)thio)ethyl)amino)-4-oxo-Butanoic acid
Other names SIG1273, TSC
Identifiers
CAS Number
3D model (JSmol)
InChI
  • InChI=1S/C27H49NO5S/c1-20(2)9-6-10-21(3)11-7-12-22(4)13-8-14-23(5)17-18-34-19-24(27(32)33)28-25(29)15-16-26(30)31/h17,20-22,24H,6-16,18-19H2,1-5H3,(H,28,29)(H,30,31)(H,32,33)i
SMILES
  • C(CCC(CCC(CCC/C(=C/CSC(NC(=O)CCC(=O)O)C(=O)O)/C)C)C)(C)C
Properties
Chemical formula C27H49NO5S
Molar mass 499.75 g·mol
log P 6.79
Specific Surface Area 129.00
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). Infobox references
Chemical compound

SIG1273 or Tetramethylhexadecenyl Succinyl Cysteine (TSC) is an isoprenylcysteine (IPC) cosmetic functional ingredient (CFI). Similar to first generation CFI, N-acetyl-farnesyl-cysteine (Arazine™), whose anti-inflammatory activities were discovered at Princeton University by Professor Jeffry B. Stock, SIG1273 also has strong anti-inflammatory properties. In addition, SIG1273 is the first IPC molecule to demonstrate anti-aging, antibacterial and anti-acne activity. In mobilizing a protective response from environmental stressors, several different cell types located in the skin release and respond to pro-inflammatory cytokines ensuring skin homeostasis and health. However, chronic activation of this response, eventually causes damage resulting in premature aging. SIG1273 combats chronic inflammation by down modulating these inflammatory pathways in various cell types (keratinocytes, fibroblasts, endothelial cells, peripheral blood mononuclear cell) to protect the skin.

Anti-inflammatory action

SIG1273 has demonstrated anti-inflammatory properties in several in vitro cell based models. Using normal human epidermal keratinocytes (NHEKs), SIG1273 was shown to reduce both Propionibacterium acnes (P. acnes) and peptidoglycan (PGN) induced interleukin-8 (IL-8) production (IC50 = 3 µM and 0.3 µM respectively). Both these ligands stimulate the production of pro-inflammatory cytokines via toll-like receptor-2 (TLR2) and toll-like receptor-4 (TLR4) signaling. Additional studies performed using NHEKs demonstrates SIG1273 blocks chemical irritant 12-O-Tetradecanoylphorbol-13-acetate (TPA) induced IL-8 and tumor necrosis factor-α (TNF- α) production (IC50 = 10 nM and 11 nM respectively) as well as ultraviolet B (UVB) induced interleukin-6 (IL-6) release (IC50 = 3 µM) in a dose dependent manner. Both these inflammatory inducers have been previously shown to increase production of several pro-inflammatory mediators in keratinocytes. Previous studies have demonstrated nickel treatment of endothelial cells activates TLR4 resulting in induction of IL-6 and IL-8. Utilizing human dermal microvascular endothelial cells (HDMECs) treated with nickel leads to overproduction of IL-6 and IL-8 which were reduced in the presence of SIG1273 in a dose dependent manner (IC50 = 1 µM and 0.1 µM respectively). In addition to keratinocytes and endothelial cells, peripheral blood mononuclear cell (PBMCs), are an important component of the immune system. In particular, IL-4 and IL-17 have recently received attention as potential targets for dermal protection. In cell based studies using PBMCs, SIG1273 was shown to inhibit T-cell receptor activated IL-4 and IL-17 release in a dose dependent manner (IC50 = 0.7 µM and 0.4 µM respectively).

Anti-aging action

Matrix metalloproteinases (MMPs) are thought to be responsible for dermal photoaging in human skin. Specifically, MMP-1 or interstitial collagenase is induced by ultraviolet A (UVA) irradiation and breaks down the extracellular matrix (type I, II and III collagen) contributing to wrinkle formation. Studies using human dermal fibroblasts (HDFs) demonstrate UVA-induced pro-MMP-1 secretion is reduced dose dependently by SIG1273 (IC50 = 0.3 µM) suggesting potential anti-wrinkle activity.

Anti-acne action

SIG1273 was assessed clinically in subjects with acne prone skin. In a 30 subject randomized, double-blind controlled study 3% SIG1273 gel or vehicle was applied for 6 weeks. Improvements in the signs and symptoms of acne were observed in subjects applying SIG1273 gel, including reduction of inflammatory lesions, microcomedone counts and Sebutape® scores (suggesting SIG1273 may decrease sebum levels). In addition, given its in vitro antibacterial activity against P. acnes, facial scrubs were taken to measure colony-forming unit (CFUs) and showed those applying SIG1273 gel had a ~90% colony reduction over the length of the study, which was statistically significant when compared with the vehicle group.

Anti-microbial action

SIG1273 has been shown to possess anti-microbial properties in vitro and in vivo. SIG1273 was determined to have a minimal inhibitory concentration (MIC) of 2 µg/ml against P. acnes. Minimum bactericidal concentration (MBC) was determined by spotting on agar plates to count colony-forming units (CFUs) and results show SIG1273 at 5 µg/ml and higher to kill P. acnes. Another common pathogen for inflammatory skin conditions is Streptococcus pyogenes (S. pyogenes). SIG1273 was shown to prevent S. pyogenes growth with a MIC of 2 µg/ml.

Adverse effects

Safety and tolerability studies in human subjects have demonstrated that SIG1273 is safe when applied topically. SIG1273 at 3% was evaluated in a 100 subject human repeated insult patch test and was found to cause no skin sensitization or irritation (Product Investigations). In a separate clinical study, 16 subjects applied 3% SIG1273 gel twice daily for 6 weeks and showed no signs of irritation, redness, dryness, burning/stinging and peeling.

References

  1. Gordon, J. S.; et, al. (March 2008). "Topical N-acetyl-S-farnesyl-L-cysteine inhibits mouse skin inflammation, and unlike dexamethasone, its effects are restricted to the application site". Journal of Investigative Dermatology. 128 (3): 643–654. doi:10.1038/sj.jid.5701061. PMID 17882268.
  2. Volker, C.; et, al. (November 1991). "Effects of farnesylcysteine analogs on protein carboxyl methylation and signal transduction". Journal of Biological Chemistry. 266 (32): 21515–22. PMID 1939182.
  3. Huzoor-Akbar; et, al. (February 1993). "Protein prenylcysteine analog inhibits agonist-receptor-mediated signal transduction in human platelets". Proceedings of the National Academy of Sciences of the United States of America. 90 (3): 868–72. PMC 45771. PMID 8430099.
  4. ^ Fernández, J.R.; et, al. (December 2012). "SIG1273: a new cosmetic functional ingredient to reduce blemishes and Propionibacterium acnes in acne prone skin". Journal of Cosmetic Dermatology. 11 (4): 272–8. doi:10.1111/jocd.12002. PMID 23174050.
  5. ^ Fernández, J.R.; et, al. (February 2015). "Anti-inflammatory and anti-bacterial properties of tetramethylhexadecenyl succinyl cysteine (TSC): a skin-protecting cosmetic functional ingredient". International Journal of Cosmetic Science. 37 (1): 129–33. doi:10.1111/ics.12166. PMID 25256809.
  6. ^ Fernández, J.R.; et, al. (December 2014). "Anti-inflammatory, anti-aging and anti-bacterial properties of SIG1273: A skin protecting cosmetic functional ingredient". 39th Annual Meeting of The Japanese Society for Investigative Dermatology: 126.
  7. Borg, M.; et, al. (October 2013). "The role of cytokines in skin aging". Climacteric. 16 (5): 514–21. doi:10.3109/13697137.2013.802303. PMID 23659624.
  8. Muthusamy, V.; Piva, T.J. (January 2010). "The UV response of the skin: a review of the MAPK, NFkappaB and TNFalpha signal transduction pathways". Archives of Dermatological Research. 302 (1): 5–17. doi:10.1007/s00403-009-0994-y. PMID 19756672.
  9. Diveu, C; et, al. (December 2008). "Cytokines that regulate autoimmunity". Curr Opin Immunol. 20 (6): 663–8. doi:10.1016/j.coi.2008.09.003. PMID 18834938.
  10. Stamatas, G.N.; et, al. (September 2013). "Early inflammatory processes in the skin". Curr Mol Med. 13 (8): 1250–69. PMID 23448341.
  11. Jugeau, S.; et, al. (December 2005). "Induction of toll-like receptors by Propionibacterium acnes". British Journal of Dermatology. 153 (6): 1105–13. doi:10.1111/j.1365-2133.2005.06933.x. PMID 16307644.
  12. Kim, S. (November 2005). "Review of the innate immune response in acne vulgaris: activation of Toll-like receptor 2 in acne triggers inflammatory cytokine responses". Dermatology. 211 (3): 193–8. doi:10.1159/000087011. PMID 16205063.
  13. Nagy, I.; et, al. (November 2005). "Propionibacterium acnes and lipopolysaccharide induce the expression of antimicrobial peptides and proinflammatory cytokines/chemokines in human sebocytes". Dermatology. 211 (3): 193–8. doi:10.1016/j.micinf.2006.04.001. PMID 16797202.
  14. Cataisson, C.; et, al. (October 2006). "CXCR2 ligands and G-CSF mediate PKCalpha-induced intraepidermal inflammation". J Clin Invest. 116 (10): 2757–2766. doi:10.1172/JCI27514. PMC 1560349. PMID 16964312.
  15. Imokawa, G. (August 2009). "Mechanism of UVB-induced wrinkling of the skin: paracrine cytokine linkage between keratinocytes and fibroblasts leading to the stimulation of elastase". J Investig Dermatol Symp Proc. 14 (1): 36–43. doi:10.1038/jidsymp.2009.11. PMID 19675551.
  16. Schmidt, M.; et, al. (September 2009). "Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel". Nat Immunol. 11 (9): 3814–9. doi:10.1038/ni.1919. PMID 20711192.
  17. ^ Numerof, R.P.; Asadullah, K. (2006). "Cytokine and anti-cytokine therapies for psoriasis and atopic dermatitis". BioDrugs. 20 (2): 93–103. PMID 16626167.
  18. Herrmann, G.; et, al. (March 1993). "UVA irradiation stimulates the synthesis of various matrix-metalloproteinases (MMPs) in cultured human fibroblasts". Experimental Dermatology. 2 (2): 193–8. PMID 8156175.
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