Trodusquemine

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Trodusquemine
Trodusquemine.svg
Clinical data
Other namesMSI-1436
ATC code
  • None
Identifiers
  • [(3R,6R)-6-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-[3-[4-(3-Aminopropylamino)butylamino]propylamino]-7-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylheptan-3-yl] hydrogen sulfate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C37H72N4O5S
Molar mass 685.07 g·mol−1
3D model (JSmol)
  • C[C@H](CC[C@H](C(C)C)OS(=O)(=O)O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2[C@@H](C[C@@H]4[C@@]3(CC[C@@H](C4)NCCCNCCCCNCCCN)C)O)C
  • InChI=1S/C37H72N4O5S/c1-26(2)34(46-47(43,44)45)13-10-27(3)30-11-12-31-35-32(15-17-37(30,31)5)36(4)16-14-29(24-28(36)25-33(35)42)41-23-9-22-40-20-7-6-19-39-21-8-18-38/h26-35,39-42H,6-25,38H2,1-5H3,(H,43,44,45)/t27-,28-,29+,30-,31+,32+,33-,34-,35+,36+,37-/m1/s1
  • Key:WUJVPODXELZABP-FWJXURDUSA-N

Trodusquemine is an aminosterol (polyamine steroid conjugate) that inhibits protein tyrosine phosphatase 1B (PTP1B) activity. [1] The compound exhibits broad-spectrum antimicrobial activity [2] and numerous regenerative, neuroprotective, anti-atherosclerotic, antitumor, antiangiogenic, antiobesity, and anxiolytic properties. [3] Phase I clinical trials of trodusquemine have demonstrated good tolerability, but several planned phase II trials were halted due to financial difficulties of the developer. [4]

Contents

Chemistry

Trodusquemine is a spermine metabolite of cholesterol. The steroid ring consists of a cholestane with a hydroxyl group at C-7 and sulfate group at C-24; spermine is conjugated to the steroid moiety at C-3. It is structurally similar to squalamine, which features a spermidine moiety instead of spermine. [3]

Pharmacology

Trodusquemine is a non-competitive allosteric inhibitor of protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 1 μmol/L. [5] Inhibition of PTP1B prevents dephosphorylation of the insulin receptor, thereby increasing insulin signaling and lowering blood glucose. [4] Trodusquemine also demonstrates affinity for the dopamine transporter (IC50 0.4 μmol/L) and norepinephrine transporter (IC50 0.7 μmol/L). [5]

Trodusquemine suppresses appetite, promotes weight loss, and rescues hyperglycemia in genetic mouse models of obesity (ob/ob) and diabetes (db/db). [6] Other effects of trodusquemine include amelioration of the metabolic syndrome in mouse models of insulin resistance; [7] correction of hepatic steatosis in ob/ob mice; [8] reversal of atherosclerosis in LDLR knock-out mice; [9] inhibition of the growth of malignancy in rodents; [10] stimulation of the regeneration of tail-fin and heart muscle in zebrafish; [11] stimulation of regenerative repair of myocardial infarction and traumatic limb muscle injury in adult mice; [11] prevention of aortic valve calcification in a mouse atheroma model; [12] stimulation of T-cell anti-tumor immunity in a mouse model; [10] correction of systemic and hepatic inflammation, insulin resistance and hepatic dysfunction in horses suffering from equine metabolic syndrome. [13]

Demonstrations of trodusquemine's neuroprotective effects include reversal of memory impairment, normalization of behavior, reduction of neuronal loss and increase in healthspan and lifespan in mouse models of Alzheimer's disease; [14] reduction in alpha-synuclein aggregation and increase in healthspan and lifespan in a C.elegans model of Parkinson's disease; [15] Trodusquemine may exert its effects by targeting specific centers in the brain. [7] Trodusquemine may also have anxiolytic properties. [16]

Although the physiological basis for the healthy lifespan of certain shark species remains unknown, trodusquemine targets well-recognized aging associated processes at both the cellular level and in vivo across many species. These observations conducted in different laboratories suggest that Trodusquemine represents a novel endogenous vertebrate geroprotector. [3]

History

Trodusquemine was originally isolated from liver extracts of the spiny dogfish ( Squalus acanthias ). [2] It was discovered through a search for antimicrobial compounds in Squaliformes, which lack a robust adaptive immune system. It was hypothesized that their innate immunity might be conferred by endogenous production of antimicrobial compounds. [3]

Related Research Articles

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References

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