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Caspofungin acetate (formerly known as MK-0991; trade name: Cancidas), a cyclic lipopeptide, is a new class of antifungal drug. It is a semi-synthetic analogue of pneumocandin B0 with improved water solubility, a significant limitation in the development of the echinocandin class as pharmaceuticals. Caspofungin acts by inhibiting the synthesis of β (1,3)-D-glucan, an essential component of the cell wall of susceptible fungi. Incubation ofA. fumigatuwith a single dose of caspofungin affected the same proportion of apical and subapical branching cells for up to 72 h.The cells at the active centers for new cell wall synthesis withinA. fumigateshyphae are killed when they are exposed to caspofungin.
Physicochemical Properties
| Molecular Formula | C56H96N10O19 |
| Molecular Weight | 1213.42 |
| Exact Mass | 1092.64 |
| Elemental Analysis | C, 55.43; H, 7.97; N, 11.54; O, 25.05 |
| CAS # | 179463-17-3 |
| Related CAS # | Caspofungin;162808-62-0;Caspofungin-d4 acetate; 162808-62-0; 179463-17-3 (acetate) |
| PubChem CID | 16119813 |
| Appearance | White to off-white solid powder |
| Boiling Point | 1408.1ºC at 760 mmHg |
| Vapour Pressure | 0mmHg at 25°C |
| LogP | 0.061 |
| Hydrogen Bond Donor Count | 18 |
| Hydrogen Bond Acceptor Count | 22 |
| Rotatable Bond Count | 23 |
| Heavy Atom Count | 85 |
| Complexity | 1930 |
| Defined Atom Stereocenter Count | 16 |
| SMILES | O=C1[C@@]([H])(NC([C@@]([H])(NC([C@]2([H])C[C@H](CN2C([C@@]([H])(NC([C@H](C[C@H]([C@H](NC([C@]2([H])[C@H](CCN21)O)=O)NCCN)O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)=O)[C@H](O)C)=O)O)=O)[C@H](O)[C@H](C1C=CC(=CC=1)O)O)=O)[C@H](O)CCN.C(=O)(O)C.C(=O)(O)C |
| InChi Key | OGUJBRYAAJYXQP-AVOYSFSSSA-N |
| InChi Code | InChI=1S/C52H88N10O15.2C2H4O2/c1-5-28(2)24-29(3)12-10-8-6-7-9-11-13-39(69)56-34-26-38(68)46(55-22-21-54)60-50(75)43-37(67)19-23-61(43)52(77)41(36(66)18-20-53)58-49(74)42(45(71)44(70)31-14-16-32(64)17-15-31)59-48(73)35-25-33(65)27-62(35)51(76)40(30(4)63)57-47(34)72;2*1-2(3)4/h14-17,28-30,33-38,40-46,55,63-68,70-71H,5-13,18-27,53-54H2,1-4H3,(H,56,69)(H,57,72)(H,58,74)(H,59,73)(H,60,75);2*1H3,(H,3,4)/t28-,29+,30-,33-,34+,35+,36-,37+,38+,40+,41-,42+,43+,44+,45+,46+;;/m1../s1 |
| Chemical Name | (10S,12R)-N-((2R,6S,9S,11S,12S,14aS,15S,20R,23S,25aS)-20-((R)-3-amino-1-hydroxypropyl)-12-((2-aminoethyl)amino)-23-((1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl)-2,11,15-trihydroxy-6-((R)-1-hydroxyethyl)-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2',1'-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl)-10,12-dimethyltetradecanamide diacetate |
| Synonyms | L743872; L-743872; L 743872; MK 0991; MK-0991; MK0991; Caspofungin acetate; brand name: Cancidas. |
| 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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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
| Targets | (1→3)-β-D-glucan synthase | |
| ln Vitro |
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| ln Vivo |
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| Enzyme Assay | The echinocandin MK-0991, formerly L-743,872, is a water-soluble lipopeptide that has been demonstrated in preclinical studies to have potent activity against Candida spp., Aspergillus fumigatus, and Pneumocystis carinii. An extensive in vitro biological evaluation of MK-0991 was performed to better define the potential activities of this novel compound. Susceptibility testing with MK-0991 against approximately 200 clinical isolates of Candida, Cryptococcus neoformans, and Aspergillus isolates was conducted to determine MICs and minimum fungicidal concentrations MF(s). The MFC at which 90% of isolates are inhibited for 40 C. albicans clinical isolates was 0.5 microg/ml. Susceptibility testing with panels of antifungal agent-resistant species of Candida and C. neoformans isolates indicated that the MK-0991 MFCs for these isolates are comparable to those obtained for susceptible isolates. Growth kinetic studies of MK-0991 against Candida albicans and Candida tropicalis isolates showed that the compound exhibited fungicidal activity (i.e., a 99% reduction in viability) within 3 to 7 h at concentrations ranging from 0.06 to 1 microg/ml (0.25 to 4 times the MIC). Drug combination studies with MK-0991 plus amphotericin B found that this combination was not antagonistic against C. albicans, C. neoformans, or A. fumigatus in vitro. Studies with 0 to 50% pooled human or mouse serum established that fungal susceptibility to MK-0991 was not significantly influenced by the presence of human or mouse serum. Results from resistance induction studies suggested that the susceptibility of C. albicans was not altered by repeated exposure (40 passages) to MK-0991. Erythrocyte hemolysis studies with MK-0991 with washed and unwashed human or mouse erythrocytes indicated minimal hemolytic potential with this compound. These favorable results of preclinical studies support further studies with MK-0991 with humans.[2] | |
| Cell Assay | Effect of coating the wells of a microtiter plate with caspofungin on C. albicans biofilm formation. A modified assay was used in which the wells of a microtiter plate were directly precoated with caspofungin in order to investigate the drug's ability to prevent biofilm formation. Briefly, 200-μl volumes of caspofungin at different concentrations in sterile PBS were added to selected wells of a microtiter plate and incubated overnight at 4°C. After incubation, excess caspofungin was aspirated and the plates were washed once in sterile PBS. C. albicans 3153A cells were washed in PBS and resuspended at a concentration of 106 cells per ml in RPMI 1640. The 96-well microtiter plates were then seeded with the suspension (100 μl per well) and incubated for 24 h at 37°C to allow biofilm formation. The contents of the wells were aspirated and washed three times in sterile PBS, and the extent of biofilm formation was assessed by the XTT reduction assay and by light microscopy. The inhibitory effect of caspofungin was expressed as the percentage of the optical density (OD) of caspofungin-treated wells compared to that of control (plastic) wells for the XTT assays. Statistical analysis was performed with Student's t test. P values of <0.05 were considered statistically significant. The analyses were performed by using Prism version 3.00 for Window.[3] | |
| Animal Protocol |
1, 2, 4, or 8 mg/kg/day; i.p. Mice Rhizopus oryzae is the most common cause of zygomycosis, a life-threatening infection that usually occurs in patients with diabetic ketoacidosis. Despite standard therapy, the overall rate of mortality from zygomycosis remains >50%, and new strategies for treatment are urgently needed. The activities of caspofungin acetate (CAS) and other echinocandins (antifungal inhibitors of the synthesis of 1,3-beta-D-glucan synthase [GS]) against the agents of zygomycosis have remained relatively unexplored, especially in animal models of infection. We found that R. oryzae has both an FKS gene, which in other fungi encodes a subunit of the GS synthesis complex, and CAS-susceptible, membrane-associated GS activity. Low-dose but not high-dose CAS improved the survival of mice with diabetic ketoacidosis infected with a small inoculum but not a large inoculum of R. oryzae. Fungal burden, assessed by a novel quantitative PCR assay, correlated with increasing inocula and progression of disease, particularly later in the infection, when CFU counts did not. CAS decreased the brain burden of R. oryzae when it was given prophylactically but not when therapy was started after infection. These results indicate that CAS has significant but limited activity against R. oryzae in vivo and demonstrates an inverse dose-response effect. The potential for CAS to play a role in combination therapy against zygomycosis merits further investigation.[4] The inhibition of R. oryzae GS by CAS (caspofungin acetate ) and the discovery of an FKS homolog demonstrate that the drug target is present in this organism. CAS might be effective against R. oryzae in vivo, despite the high MIC, especially given the known constraints of MIC testing with molds (13, 29). The in vivo efficacy of CAS was tested in diabetic ketoacidotic mice infected with R. oryzae. Intravenous treatment with AMB (0.5 mg/kg b.i.d.) or CAS (0.5, 2.5, or 5 mg/kg b.i.d.) was initiated 24 h after the mice were infected with 5 × 102 or 5 × 103 spores of R. oryzae. At 0.5 mg/kg b.i.d., CAS, but not AMB, improved the survival of mice infected with 5 × 102 spores of R. oryzae compared to that of the infected untreated mice (P = 0.049) (Fig.2a). Eighty percent of the diabetic mice treated with CAS at 0.5 mg/kg/day were alive 10 days after infection, whereas 30% of the infected untreated mice were alive at that time. Surprisingly, higher doses of CAS (2.5 or 5 mg/kg b.i.d.) did not improve the rate of survival. These results indicate that CAS has significant but limited activity against R. oryzae in vivo and demonstrates an inverse dose-response effect. [4] |
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| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the use of caspofungin during breastfeeding. Because caspofungin is 97% bound to plasma proteins and has poor oral bioavailability, it is unlikely to reach the milk and be absorbed by the infant. Caspofungin can safely be given intravenously to infants of aged 3 months or older. Any amount absorbed from milk is likely to be far less than an infant dose. If caspofungin is required by the mother, it is not a reason to discontinue breastfeeding. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. |
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| References |
[1]. Crit Care Med.2003 May;31(5):1577-8; [2]. Antimicrob Agents Chemother.1997 Nov;41(11):2326-32. [3]. Antimicrob Agents Chemother. 2002 Nov; 46(11): 3591–3596. [4]. Antimicrob Agents Chemother. 2005 Feb; 49(2): 721–727. |
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| Additional Infomation |
Caspofungin Acetate is the acetate salt of an antimycotic echinocandin lipopeptide, semisynthetically derived from a fermentation product of the fungus Glarea lozoyensis. Caspofungin inhibits 1,3-beta-glucan synthase, resulting in decreased synthesis of beta(1,3)-D-glucan (an essential component of the fungal cell wall), weakening of the fungal cell wall, and fungal cell wall rupture. This agent is active against Aspergillus and Candida species. A cyclic lipopeptide echinocandin and beta-(1,3)-D-glucan synthase inhibitor that is used to treat internal or systemic MYCOSES. See also: Caspofungin (has active moiety). Drug Indication Treatment of invasive candidiasis in adult or paediatric patients. Treatment of invasive aspergillosis in adult or paediatric patients who are refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B and/or itraconazole. Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy. Empirical therapy for presumed fungal infections (such as Candida or Aspergillus) in febrile, neutropaenic adult or paediatric patients. Fungal infections |
Solubility Data
| Solubility (In Vitro) |
DMSO : 100 mg/mL ( 82.41 mM ) Water : 50~100 mg/mL (~82.41 mM ) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.06 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (1.71 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (1.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 10% DMSO+90% (20% SBE-β-CD in Saline): ≥ 2.5 mg/mL (2.06 mM) Solubility in Formulation 5: 100 mg/mL (82.41 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.8241 mL | 4.1206 mL | 8.2412 mL | |
| 5 mM | 0.1648 mL | 0.8241 mL | 1.6482 mL | |
| 10 mM | 0.0824 mL | 0.4121 mL | 0.8241 mL |