 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C256H381N65O76S6 |
| Molecular Weight | 5777.54429221153 |
| Exact Mass | 5791.628 |
| CAS # | 12584-58-6 |
| PubChem CID | 70678557 |
| Appearance | White to off-white solid powder |
| LogP | -12.8 |
| Hydrogen Bond Donor Count | 78 |
| Hydrogen Bond Acceptor Count | 89 |
| Rotatable Bond Count | 178 |
| Heavy Atom Count | 404 |
| Complexity | 14600 |
| Defined Atom Stereocenter Count | 52 |
| SMILES | S1C[C@@H](C(NCC(N[C@@H](CCC(=O)O)C(N[C@@H](CCCNC(=N)N)C(NCC(N[C@@H](CC2C=CC=CC=2)C(N[C@@H](CC2C=CC=CC=2)C(N[C@@H](CC2C=CC(=CC=2)O)C(N[C@@H]([C@@H](C)O)C(N2CCC[C@H]2C(N[C@H](C(N[C@H](C(=O)O)C)=O)CCCCN)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)NC([C@H](C(C)C)NC([C@H](CC(C)C)NC([C@H](CC2C=CC(=CC=2)O)NC([C@H](CC(C)C)NC([C@H](C)NC([C@H](CCC(=O)O)NC([C@H](C(C)C)NC([C@H](CC(C)C)NC([C@H](CC2=CN=CN2)NC([C@H](CO)NC(CNC([C@H](CSSC[C@H]2C(N[C@@H]([C@@H](C)O)C(N[C@@H](CO)C(N[C@H](C(N[C@@H](CSSC[C@@H](C(N2)=O)NC([C@H](CCC(N)=O)NC([C@H](CCC(=O)O)NC([C@H](C(C)C)NC([C@H]([C@@H](C)CC)NC(CN)=O)=O)=O)=O)=O)C(N[C@@H](CO)C(N[C@H](C(N[C@H](C(N[C@@H](CCC(N)=O)C(N[C@H](C(N[C@H](C(N[C@@H](CC(N)=O)C(N[C@@H](CC2C=CC(=CC=2)O)C(N[C@H](C(N[C@H](C(=O)O)CC(N)=O)=O)CS1)=O)=O)=O)CCC(=O)O)=O)CC(C)C)=O)=O)CC1C=CC(=CC=1)O)=O)CC(C)C)=O)=O)=O)[C@@H](C)CC)=O)=O)=O)NC([C@H](CC(C)C)NC([C@H](CC1=CN=CN1)NC([C@H](CCC(N)=O)NC([C@H](CC(N)=O)NC([C@H](C(C)C)NC([C@H](CC1C=CC=CC=1)N)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O |
| InChi Key | YAJCHEVQCOHZDC-QMMNLEPNSA-N |
| InChi Code | InChI=1S/C256H381N65O77S6/c1-29-130(23)202(311-190(337)103-258)250(391)315-200(128(19)20)246(387)286-158(75-82-197(347)348)216(357)281-154(70-77-186(261)333)220(361)306-181-115-402-403-116-182-241(382)303-176(110-323)238(379)293-161(88-122(7)8)224(365)294-167(95-139-53-61-145(328)62-54-139)227(368)282-153(69-76-185(260)332)217(358)289-160(87-121(5)6)222(363)283-157(74-81-196(345)346)219(360)301-173(101-188(263)335)233(374)297-169(97-141-57-65-147(330)66-58-141)230(371)307-180(240(381)302-174(254(395)396)102-189(264)336)114-401-400-113-179(213(354)272-106-191(338)277-152(72-79-194(341)342)215(356)280-150(51-42-84-270-256(266)267)211(352)271-107-192(339)278-165(93-137-46-36-32-37-47-137)226(367)296-166(94-138-48-38-33-39-49-138)229(370)298-170(98-142-59-67-148(331)68-60-142)236(377)318-205(134(27)326)253(394)321-85-43-52-184(321)244(385)284-151(50-40-41-83-257)221(362)319-206(135(28)327)255(397)398)309-247(388)199(127(17)18)314-234(375)163(90-124(11)12)291-228(369)168(96-140-55-63-146(329)64-56-140)295-223(364)159(86-120(3)4)288-209(350)132(25)276-214(355)156(73-80-195(343)344)285-245(386)198(126(15)16)313-235(376)164(91-125(13)14)292-232(373)172(100-144-105-269-119-275-144)300-237(378)175(109-322)279-193(340)108-273-212(353)178(112-399-404-117-183(308-242(181)383)243(384)317-204(133(26)325)251(392)304-177(111-324)239(380)316-203(131(24)30-2)249(390)310-182)305-225(366)162(89-123(9)10)290-231(372)171(99-143-104-268-118-274-143)299-218(359)155(71-78-187(262)334)287-252(393)207(208(265)349)320-248(389)201(129(21)22)312-210(351)149(259)92-136-44-34-31-35-45-136/h31-39,44-49,53-68,104-105,118-135,149-184,198-207,322-331H,29-30,40-43,50-52,69-103,106-117,257-259H2,1-28H3,(H2,260,332)(H2,261,333)(H2,262,334)(H2,263,335)(H2,264,336)(H2,265,349)(H,268,274)(H,269,275)(H,271,352)(H,272,354)(H,273,353)(H,276,355)(H,277,338)(H,278,339)(H,279,340)(H,280,356)(H,281,357)(H,282,368)(H,283,363)(H,284,385)(H,285,386)(H,286,387)(H,287,393)(H,288,350)(H,289,358)(H,290,372)(H,291,369)(H,292,373)(H,293,379)(H,294,365)(H,295,364)(H,296,367)(H,297,374)(H,298,370)(H,299,359)(H,300,378)(H,301,360)(H,302,381)(H,303,382)(H,304,392)(H,305,366)(H,306,361)(H,307,371)(H,308,383)(H,309,388)(H,310,390)(H,311,337)(H,312,351)(H,313,376)(H,314,375)(H,315,391)(H,316,380)(H,317,384)(H,318,377)(H,319,362)(H,320,389)(H,341,342)(H,343,344)(H,345,346)(H,347,348)(H,395,396)(H,397,398)(H4,266,267,270)/t130-,131-,132+,133+,134+,135+,149+,150+,151+,152+,153+,154+,155+,156+,157+,158+,159+,160+,161+,162+,163+,164+,165+,166+,167+,168+,169+,170+,171+,172+,173+,174+,175+,176+,177+,178+,179+,180+,181+,182-,183+,184+,198+,199+,200+,201+,202+,203+,204+,205+,206+,207+/m1/s1 |
| Chemical Name | (4S)-4-[[2-[[(1R,6R,12S,15S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,50S,53S,56S,59S,62S,65S,68S,71S,74S,77S,80S,83S,88R)-88-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[(2-aminoacetyl)amino]-3-methylpentanoyl]amino]-3-methylbutanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]-6-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-3-amino-2-[[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-3-oxopropanoyl]amino]-5-oxopentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-4-methylpentanoyl]amino]-47-[[(1S)-3-amino-1-carboxy-3-oxopropyl]carbamoyl]-53-(2-amino-2-oxoethyl)-62-(3-amino-3-oxopropyl)-77-[(2R)-butan-2-yl]-24,56-bis(2-carboxyethyl)-83-[(1S)-1-hydroxyethyl]-12,71,80-tris(hydroxymethyl)-33,50,65-tris[(4-hydroxyphenyl)methyl]-15-(1H-imidazol-4-ylmethyl)-27-methyl-18,30,36,59,68-pentakis(2-methylpropyl)-7,10,13,16,19,22,25,28,31,34,37,40,49,52,55,58,61,64,67,70,73,76,79,82,85,87-hexacosaoxo-21,39-di(propan-2-yl)-3,4,44,45,90,91-hexathia-8,11,14,17,20,23,26,29,32,35,38,41,48,51,54,57,60,63,66,69,72,75,78,81,84,86-hexacosazabicyclo[72.11.7]dononacontane-42-carbonyl]amino]acetyl]amino]-5-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[(2S)-2-[[(2S)-6-amino-1-[[(1S,2S)-1-carboxy-2-hydroxypropyl]amino]-1-oxohexan-2-yl]carbamoyl]pyrrolidin-1-yl]-3-hydroxy-1-oxobutan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-oxopentanoic acid |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion FRACTION OF...EXOGENOUS INSULIN IN PLASMA MAY BE ASSOC WITH CERTAIN PROTEINS, CHIEFLY ALPHA- & BETA-GLOBULINS. ...THESE ASSOC ARE OF IMPORTANCE FOR TRANSPORT OF INSULIN...WHICH APPEARS TO CIRCULATE IN BLOOD & LYMPH... VOL OF DISTRIBUTION OF INSULIN APPROXIMATES VOL OF EXTRACELLULAR FLUID. WHILE INSULIN CAN BE DETECTED IN URINE, THE KIDNEY FILTERS & REABSORBS THE HORMONE & RENAL EXCRETION IS NOT MAJOR ROUTE OF ELIMINATION. LIVER & KIDNEY ARE OF PRIMARY IMPORTANCE IN DEGRADING HORMONE & EACH IS CAPABLE OF DESTROYING ALMOST 40% OF INSULIN PRODUCED PER DAY (30 TO 50 UNITS). SEVERE IMPAIRMENT OF RENAL FUNCTION APPEARS TO AFFECT RATE OF DISAPPEARANCE OF CIRCULATING INSULIN TO GREATER EXTENT THAN DOES HEPATIC DISEASE... IN ABSENCE OF INSULIN THERE IS MARKED REDUCTION IN RATE OF TRANSPORT OF GLUCOSE ACROSS CERTAIN CELL MEMBRANES. SERIAL IMMUNOREACTIVE INSULIN CONCN WERE MUCH HIGHER AFTER EXERCISE THAN THOSE ASSOC WITH REST. THE ENHANCED ABSORPTION OF INSULIN FROM SC TISSUE IS PROBABLY THROUGH AN INCR IN BLOOD FLOW IN INJECTED LIMB. Metabolism / Metabolites IN-VITRO EXPT SUGGESTS 2 SYSTEMS INVOLVED IN DEGRADATION OF INSULIN BY LIVER: (1) ENZYME TERMED GLUTATHIONE-INSULIN TRANSHYDROGENASE, WHICH UTILIZES REDUCED GLUTATHIONE TO REDUCE DISULFIDE BRIDGES; & (2) PROTEOLYTIC ENZYME(S) THAT CLEAVES REDUCED & SEPARATED CHAINS TO PEPTIDES & AMINO ACIDS. A PROTEOLYTIC ENZYME THAT DEGRADES BOTH INSULIN & GLUCAGON HAS BEEN EXTENSIVELY PURIFIED FROM RAT SKELETAL MUSCLE. A fraction of exogenous insulin in plasma may be associated with certain proteins, chiefly alpha- and beta-globulins. These associations are of importance for the transport of insulin, which appears to circulate in the blood and the lymph. It is proposed that two systems are involved in the degradation of insulin by liver.(1) The glutathione-insulin transhydrogenase, which utilizes reduced glutathione to reduce disulfide bridges.(2) Proteolic enzymes that cleaves reduced and separated chains to peptides and amino acids. While Insulin is partly excreted in the urine, the kidney filters and reabsorbs the hormone and renal excretion is not the major route of elimination. Liver and kidney are of primary importance in degrading the hormone and each is capable of destroying a large part of the insulin produced daily. (T167). Biological Half-Life PLASMA HALF-LIFE OF INSULIN INJECTED INTRAVENOUSLY IS LESS THAN 9 MINUTES IN MAN. |
| Toxicity/Toxicokinetics |
Hepatotoxicity Insulin in typical therapeutic doses is not associated with serum enzyme elevations or with episodes of clinically apparent liver injury. However, use of insulin in poorly controlled type 1 diabetes can result in a clinical syndrome known as glycogenosis or glycogenic hepatopathy, marked by varying degrees of hepatomegaly, abdominal pain and serum aminotransferase elevations. Serum ALT and AST levels range from normal to 20 to 30 times the upper limit or normal. Alkaline phosphatase and bilirubin levels are minimally increased or normal. Serum glucose and hemoglobin A1c levels are invariably elevated, and the liver and metabolic abnormalities resolve rapidly with better glycemic control. A severe form of glycogenosis associated with hepatomegaly, growth retardation, delayed puberty and Cushingoid facies in children is known as Mauriac syndrome. Glycogenosis with serum enzyme elevations can also occur in patients with insulin overdose during treatment with high doses of intravenous glucose (Case 1). Glycogenosis has also been reported in patients recieving short-term, high-dose corticosteroids.. The diagnosis of glycogenosis can be confirmed by liver biopsy which typically shows slightly swollen hepatocytes with pale cytoplasm and accentuated cell membranes, which with periodic acid Schiff (PAS) staining demonstrates intracytoplasmic accumulation of glycogen. Imaging by CT usually shows an enlarged and hyper-dense liver in contrast to hepatic steatosis which generally causes a hypo-dense pattern. The condition can be relapsing, accompanying repeated episodes of hyperglycemia, but it does not appear to result in chronic liver injury, fibrosis or cirrhosis. Thus, the serum enzyme elevations are due to the combination of marked hyperglycemia and intermittent or high levels of insulin and not to intrinsic hepatotoxicity or an idiosyncratic reaction to insulin. The syndrome occurs most commonly in children or young adults with poorly controlled type 1 diabetes. Likelihood score: A[H] (known cause of liver injury, but only when administered in high or intermittent doses and in the presence of hyperglycemia). |
| References |
[1]. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10252-6. |
| Additional Infomation |
Insulin is a pancreatic hormone that plays an essential role in regulation of blood glucose as well as lipid and carbohydrate metabolism. Both natural and recombinant forms of insulin are used therapeutically to treat type 1 diabetes. While insulin itself is not hepatotoxic and has not been linked to serum enzyme elevations or instances of clinically apparent liver injury, high doses including overdoses of insulin and glucose can result in hepatic glycogenosis and serum aminotransferase elevations. Insulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. It is a peptide hormone composed of 51 amino acid residues and has a molecular weight of 5808 Da. It is produced in the islets of Langerhans in the pancreas. When insulin is absent (or low), glucose is not taken up by body cells, and the body begins to use fat as an energy source (L1006). A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1). Mechanism of Action INSULIN HAS DIRECT INHIBITORY EFFECT ON LIPASE CONCERNED WITH MOBILIZATION OF FATTY ACIDS, WHILE GROWTH HORMONE, GLUCOCORTICOIDS, THYROID HORMONES & CATECHOLAMINES ENHANCE LIPOLYSIS. IN ABSENCE OF INSULIN THERE IS ABNORMALLY HIGH RATE OF CONVERSION OF PROTEIN TO GLUCOSE. ... PROTEINS & AMINO ACIDS ARE CONVERTED TO GLUCOSE @ ABNORMALLY HIGH RATE IN INSULIN DEFICIENCY. THE LIVER IS SITE OF CONVERSION. PROTEIN & AMINO ACIDS ARE MOBILIZED FROM PERIPHERAL TISSUES. INSULIN ACTS TO.../STIMULATE/ GLYCOGEN SYNTHESIS. MECHANISM OF IMPORTANT ACTIONS OF INSULIN TO ENHANCE FACILITATED DIFFUSION OF GLUCOSE & ACTIVE TRANSPORT OF AMINO ACIDS ARE NOT KNOWN. |
Solubility Data
| Solubility (In Vitro) | May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.1731 mL | 0.8654 mL | 1.7308 mL | |
| 5 mM | 0.0346 mL | 0.1731 mL | 0.3462 mL | |
| 10 mM | 0.0173 mL | 0.0865 mL | 0.1731 mL |