Incyclinide
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MedKoo CAT#: 201520

CAS#: 15866-90-7

Description: Iincyclinide, also known as CMT-3 and COL-3, is a MMP inhibitor and a chemically-modified tetracycline with potential antineoplastic activity. Incyclinide inhibits matrix metalloproteinases (MMPs), thereby inducing extracellular matrix degradation, and inhibiting angiogenesis, tumor growth and invasion, and metastasis. This agent also causes mitochondrial depolarization in tumor cells and induces both cellular apoptosis and tissue necrosis.


Chemical Structure

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Incyclinide
CAS# 15866-90-7

Theoretical Analysis

MedKoo Cat#: 201520
Name: Incyclinide
CAS#: 15866-90-7
Chemical Formula: C19H17NO7
Exact Mass: 371.1005
Molecular Weight: 371.34
Elemental Analysis: C, 61.45; H, 4.61; N, 3.77; O, 30.16

Price and Availability

Size Price Availability Quantity
5.0mg USD 150.0 Same day
10.0mg USD 250.0 Same day
25.0mg USD 550.0 Same day
50.0mg USD 950.0 Same day
100.0mg USD 1650.0 Same day
200.0mg USD 2950.0 Same day
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Synonym: CMT-3; CMT 3; CMT3; COL3; COL-3; COL 3; Incyclinide; 4-dedimethylamino sancycline; Chemically modified tetracycline-3. US brand name: Metastat.

IUPAC/Chemical Name: (4aS,5aR,12aS)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide

InChi Key: ZXFCRFYULUUSDW-OWXODZSWSA-N

InChi Code: InChI=1S/C19H17NO7/c20-18(26)14-11(22)6-9-5-8-4-7-2-1-3-10(21)12(7)15(23)13(8)16(24)19(9,27)17(14)25/h1-3,8-9,21-22,24,27H,4-6H2,(H2,20,26)/t8-,9-,19-/m0/s1

SMILES Code: O=C(C1=C(O)C[C@@](C[C@@]2([H])C(C(C3=C(O)C=CC=C3C2)=O)=C4O)([H])[C@@]4(O)C1=O)N

Appearance: Yellow solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Incyclinide (CMT-3, COL-3) is a matrix metalloproteinase (MMP) inhibitor.
In vitro activity: CMT-3 (6-demethyl, 6-deoxy, 4-dedimethylamino TC) has been shown to experimentally suppress prostate cancer, colon adenocarcinoma and melanoma invasiveness in cell culture and to inhibit tumor growth and metastasis in vivo and was used in the current in vitro study. Confluent MT1-MMP transfected COS-1 cells were harvested, washed thoroughly, subjected to N(2) cavitation and cell membrane enriched fractions were isolated by sequential centrifugations. This MT1-MMP preparation exhibited (i) pro-MMP-2 activating activity as shown by molecular weight shift of this gelatinase from 72 kDa to 62 kDa using gelatin zymography, and (ii) the ability to degrade both [(3)H-methyl] gelatin and casein at 37 degrees C. Adding CMT-3 at final concentrations of 5--20microM inhibited MT1-MMP gelatinolytic and caseinolytic activity, blocked MT1-MMP activation of pro-MMP-2, and decreased invasiveness (using the Matrigel system) of HT-1080 fibrosarcoma cells. The inhibition of MT1-MMP by CMT-3 may partially explain the inhibition of cancer cell -mediated tissue breakdown and invasiveness by this non-antimicrobial tetracycline analog. Reference: Curr Med Chem. 2001 Feb;8(3):257-60. https://www.eurekaselect.com/https://www.eurekaselect.com/64850/article
In vivo activity: Rats were implanted with radiotelemetry devices for recording mean arterial pressure. Ang II (angiotensin II) was infused subcutaneously using osmotic mini-pumps to induce hypertension. Another osmotic mini-pump was surgically implanted to infuse CMT-3 intracerebroventricularly. Intracerebroventricular CMT- 3 infusion was also investigated in SHR (spontaneously hypertensive rats). Physiological, pathological, immunohistological parameters, and fecal microbiota were analyzed. Intracerebroventricular CMT-3 significantly inhibited Ang II-induced increases in number of microglia, their activation, and proinflammatory cytokines in the paraventricular nucleus of hypothalamus. Further, intracerebroventricular CMT-3 attenuated increased mean arterial pressure, normalized sympathetic activity, and left ventricular hypertrophy in Ang II rats, as well as in the SHR. Finally, CMT-3 beneficially restored certain gut microbial communities altered by Ang II and attenuated pathological alterations in gut wall. Reference: Circ Res. 2019 Mar;124(5):727-736. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30612527/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 269.29

Preparing Stock Solutions

The following data is based on the product molecular weight 371.34 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. Lee HM, Golub LM, Cao J, Teronen O, Laitinen M, Salo T, Zucker S, Sorsa T. CMT-3, a non-antimicrobial tetracycline (TC), inhibits MT1-MMP activity: relevance to cancer. Curr Med Chem. 2001 Feb;8(3):257-60. doi: 10.2174/0929867013373660. PMID: 11172680. 2. Liu Y, Ryan ME, Lee HM, Simon S, Tortora G, Lauzon C, Leung MK, Golub LM. A chemically modified tetracycline (CMT-3) is a new antifungal agent. Antimicrob Agents Chemother. 2002 May;46(5):1447-54. doi: 10.1128/AAC.46.5.1447-1454.2002. PMID: 11959581; PMCID: PMC127171.
In vivo protocol: 1. Sharma RK, Yang T, Oliveira AC, Lobaton GO, Aquino V, Kim S, Richards EM, Pepine CJ, Sumners C, Raizada MK. Microglial Cells Impact Gut Microbiota and Gut Pathology in Angiotensin II-Induced Hypertension. Circ Res. 2019 Mar;124(5):727-736. doi: 10.1161/CIRCRESAHA.118.313882. PMID: 30612527; PMCID: PMC6395495. 2. Vieira GM, Falcao DP, de Queiroz SBF, de Lima VN, Bentes de Azevedo R, Tiziane V, Moreno H, Amorim R. A Novel Analysis via Micro-CT Imaging Indicates That Chemically Modified Tetracycline-3 (CMT-3) Inhibits Tooth Relapse after Orthodontic Movement: A Pilot Experimental Study. Int J Dent. 2019 Apr 1;2019:3524207. doi: 10.1155/2019/3524207. PMID: 31065268; PMCID: PMC6466921.

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1: Edan RA, Luqmani YA, Masocha W. COL-3, a chemically modified tetracycline, inhibits lipopolysaccharide-induced microglia activation and cytokine expression in the brain. PLoS One. 2013;8(2):e57827. doi: 10.1371/journal.pone.0057827. Epub 2013 Feb 28. PubMed PMID: 23469077; PubMed Central PMCID: PMC3585197.

2: Parvathy SS, Masocha W. Matrix metalloproteinase inhibitor COL-3 prevents the development of paclitaxel-induced hyperalgesia in mice. Med Princ Pract. 2013;22(1):35-41. doi: 10.1159/000341710. Epub 2012 Aug 16. PubMed PMID: 22907189.

3: Rudek MA, New P, Mikkelsen T, Phuphanich S, Alavi JB, Nabors LB, Piantadosi S, Fisher JD, Grossman SA. Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas. J Neurooncol. 2011 Nov;105(2):375-81. doi: 10.1007/s11060-011-0602-9. Epub 2011 May 6. PubMed PMID: 21547395; PubMed Central PMCID: PMC3197967.

4: Chu QS, Forouzesh B, Syed S, Mita M, Schwartz G, Cooper J, Curtright J, Rowinsky EK. A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas. Invest New Drugs. 2007 Aug;25(4):359-67. Epub 2007 Jan 20. Erratum in: Invest New Drugs. 2007 Aug;25(4):357. Copper, Joshua [corrected to Cooper, Joshua]. PubMed PMID: 17237909.

5: Halter JM, Pavone LA, Steinberg JM, Gatto LA, DiRocco J, Landas S, Nieman GF. Chemically modified tetracycline (COL-3) improves survival if given 12 but not 24 hours after cecal ligation and puncture. Shock. 2006 Dec;26(6):587-91. PubMed PMID: 17117134.

6: Muir P, Manley PA, Hao Z. COL-3 inhibition of collagen fragmentation in ruptured cranial cruciate ligament explants from dogs with stifle arthritis. Vet J. 2007 Sep;174(2):403-6. Epub 2006 Sep 15. PubMed PMID: 16978892.

7: Furlow B. COL-3 benefits patients with AIDS-related Kaposi's sarcoma. Lancet Oncol. 2006 May;7(5):368. PubMed PMID: 16696161.

8: Dezube BJ, Krown SE, Lee JY, Bauer KS, Aboulafia DM. Randomized phase II trial of matrix metalloproteinase inhibitor COL-3 in AIDS-related Kaposi's sarcoma: an AIDS Malignancy Consortium Study. J Clin Oncol. 2006 Mar 20;24(9):1389-94. PubMed PMID: 16549833.

9: Onoda T, Ono T, Dhar DK, Yamanoi A, Nagasue N. Tetracycline analogues (doxycycline and COL-3) induce caspase-dependent and -independent apoptosis in human colon cancer cells. Int J Cancer. 2006 Mar 1;118(5):1309-15. PubMed PMID: 16152604.

10: Li J, Zhou S, Huynh H, Duan W, Chan E. Alteration of the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, due to acute gastrointestinal toxicity of doxorubicin. Pharm Res. 2005 Nov;22(11):1954-63. Epub 2005 Aug 13. PubMed PMID: 16086226.

11: Li J, Zhou S, Huynh H, Chan E. Significant intestinal excretion, one source of variability in pharmacokinetics of COL-3, a chemically modified tetracycline. Pharm Res. 2005 Mar;22(3):397-404. PubMed PMID: 15835745.

12: Rudek MA, Hartke C, Zabelina Y, Zhao M, New P, Baker SD. A sensitive method for determination of COL-3, a chemically modified tetracycline, in human plasma using high-performance liquid chromatography and ultraviolet detection. J Pharm Biomed Anal. 2005 Apr 1;37(4):751-6. Epub 2004 Dec 29. PubMed PMID: 15797797.

13: Syed S, Takimoto C, Hidalgo M, Rizzo J, Kuhn JG, Hammond LA, Schwartz G, Tolcher A, Patnaik A, Eckhardt SG, Rowinsky EK. A phase I and pharmacokinetic study of Col-3 (Metastat), an oral tetracycline derivative with potent matrix metalloproteinase and antitumor properties. Clin Cancer Res. 2004 Oct 1;10(19):6512-21. PubMed PMID: 15475438.

14: Li J, Huynh H, Chan E. Reversed-phase liquid chromatography method to determine COL-3, a matrix metalloproteinase inhibitor, in biological samples. J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Jan 25;799(2):311-21. PubMed PMID: 14670750.

15: Rudek MA, Venitz J, Ando Y, Reed E, Pluda JM, Figg WD. Factors involved in the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer: clinical and experimental studies. J Clin Pharmacol. 2003 Oct;43(10):1124-35. PubMed PMID: 14517195.

16: Chen YL, Hanson GD, Weng N, Powala C, Zerler B. Quantification of 6-deoxy-6-demethyl-4-dedimethylaminotetracycline (COL-3) in human plasma using liquid chromatography coupled with electrospray ionization tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Aug 25;794(1):77-88. PubMed PMID: 12888200.

17: Li J, Huynh H, Chan E. Evidence for dissolution rate-limited absorption of COL-3, a matrix metalloproteinase inhibitor, leading to the irregular absorption profile in rats after oral administration. Pharm Res. 2002 Nov;19(11):1655-62. PubMed PMID: 12458671.

18: Lokeshwar BL, Selzer MG, Zhu BQ, Block NL, Golub LM. Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non-antimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model. Int J Cancer. 2002 Mar 10;98(2):297-309. PubMed PMID: 11857423.

19: Cianfrocca M, Cooley TP, Lee JY, Rudek MA, Scadden DT, Ratner L, Pluda JM, Figg WD, Krown SE, Dezube BJ. Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi's sarcoma: a phase I AIDS malignancy consortium study. J Clin Oncol. 2002 Jan 1;20(1):153-9. PubMed PMID: 11773164.

20: Ghate JV, Turner ML, Rudek MA, Figg WD, Dahut W, Dyer V, Pluda JM, Reed E. Drug-induced lupus associated with COL-3: report of 3 cases. Arch Dermatol. 2001 Apr;137(4):471-4. PubMed PMID: 11295928.



Additional Information

 
 
Information about this agent
The chemically modified tetracycline (CMT) incyclinide (COL-3, CMT-3) has been extensively studied as a potential new therapeutic agent for allergic conditions, inflammatory (i.e., arthritis, acute respiratory distress syndrome [ARDS], septic shock syndrome, acne and rosacea), neoplastic (i.e., Kaposi's sarcoma, colon carcinoma, melanoma, prostate cancer) and infectious (fungal) diseases. The most prominent characteristic of CMTs is their lack of antibacterial properties, accompanied by retention, or even enhancement, of metalloproteinase (MMP) inhibition. Studies have demonstrated that incyclinide is a modulator of MMP-2, MMP-9 and serine proteases, as well as cytokines and interleukins that are crucial in the development of inflammation, angiogenesis and tum origenesis. Furthermore, toxicology studies have demonstrated that incyclinide is relatively safe. See Drugs Fut 2007, 32(3): 209.