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Thapsic Acid
CAS
505-54-4
PubChem ID
10459
Molecular Formula
C16H30O4

Thapsic acid, also known as 1,14-Tetradecanedicarboxylic acid or 1,16-Hexadecanedioic acid, is an unbranched long chain fatty acid with carboxylic(COO–) groups at C1 and C14 or C16 position. It is one of the lesser known dicarboxylic acids much like aspartic acid and glutamic acid, two essential amino acids of the human body. Although considered as a toxic compound due to its presence in human feces and urine, esters of Hexadecanedioic acid have been tested for improving the antitumor activity.

PharmaCompass offers information on [1,16-Hexadecanedioic acid, CAS Number 505-54-4] for your research and manufacturing needs. Find product specific information including suppliers, manufacturers, chemical information CAS, MSDS, protocols and references.

Physical, Chemical and Biological Characteristics

In plants, hexadecanedioic acid is found in the dry roots of a Mediterranean shrub, Thapsia garganica. This chemical compound is soluble in ether and carbon disulphide and non-soluble in water. It has a poisonous smell and forms white precipitates with Hydrochloric acid.

Hexadecanedioic acid exists as a solid naturally with a melting point of 120–123°C. It has absorbance peaks between 2910 cm­-1 and 2930 cm-1 with Potassium Bromide wafer and Vapor Phase spectroscopy techniques, respectively. It weighs 286.4 grams per mole and is an uncharged molecule at normal pH. The storage temperature for this dicarboxylic acid is restricted to 2–8°C.Hexadecanedioic acid is an intermediate compound used in preparation of flavouring and fragrance compounds. Hexadecanedioic acid intermediate is used by chemical manufacturers in industrial production of Exaltone.

Other Dicarboxylic acids are as described below:

C length (Straight)

Product

CAS #

Melting Point

Boiling Point

C 2

Oxalic Acid (Ethanedioic Acid)

144-62-7

189 - 191 C

Sublimes

C 3

Malonic Acid (Propanedioic Acid)

141-82-2

131 - 135 C

Decomposes

C 4

Succinic Acid (Butanedioic Acid)

110-15-6

185 - 190 C

235 C

C 5

Glutaric Acid (Pentanedioic Acid)

110-94-1

95 - 99 C

302 C

C 6

Adipic Acid  (Hexanedioic Acid)

124-04-9

151 - 153 C

265 C at 100 mmHg

C 7

Pimelic Acid (Heptanedioic Acid)

111-16-0

105 - 106 C

212 C at 10 mmHg

C 8

Suberic Acid (Octanedioic Acid)

505-48-6

143 - 144 C

230 C at 15 mmHg

C 9

Azelaic Acid (Nonanedioic Acid)

123-99-9

100 - 103 C

237 C at 15 mmHg

C 10

Sebacic Acid (Decanedioic Acid)

111-20-6

131 - 134 C

294 at 100 mmHg

C 11

Undecanedioic acid

1852-04-6

109 - 110 C

C 12

Dodecanedioic acid

693-23-2

128 - 129 C

245 C at 10 mmHg

C 13

Brassylic acid (Tridecanedioic acid)

505-52-2

112 - 114 C

C 14

Tetradecanedioic acid

821-38-5

126 - 128 C

C 15

Pentadecanedioic acid

1460-18-0

C 16

Thapsic acid (Hexadecanedioic acid)

505-54-4

124 - 126 C

C 18

Octadecanedioic acid

871-70-5


Hexadecanedioic acid is produced in the liver of a patient with ketosis by ?-oxidation of long-chain monocarboxylic acids and their subsequent degradation. Hexadecanedioic acid is a simplefat containing only saturated CH­2—CH2 bonds and terminal –COOH groups. It is not a useful fat for the human body like omega-3 fatty acids. Since it accumulates in the ketone bodies as a result of fat metabolism in the liver, sometimes it is considered as a toxic chemical as well. It has serious adverse effects such as skin corrosion/burning/irritation, eye irritation/damage, respiratory tract irritation, and organ toxicity.

Industrial Applications

Thapsic acid is useful for synthesis of Exaltone, which is a scenting substance used extensively in the perfume industry. It belongs to the class of ‘specialty chemicals’ and can be only used as an industrial starting compound. Currently, there are more than 50 chemical manufacturers of Hexadecanedioic acid globally. Among chemical manufacturers of Thapsic acid, the predominant Hexadecanedioic acid suppliers in India are present in the North and West Indian states of Delhi and Maharashtra. It is such a sought after chemical product for the flavoring and fragrance industries who look at alternative chemical suppliers and distributors for more feasible bulk supplies. The beauty and cosmetics segment recognizes Thapsic acid as a starting compound to generate musk-based compounds added to beauty products. Other possible applications of Hexadecanedioic acid include experimentation and testing of the anticancer properties of its esters in comparison with 4'-demethyl-4-deoxypodophyllotoxin (DDPT). It is also used as an in vivo metabolic biomarker for understanding drug toxicities in the human liver through transporter-mediated drug–drug interactions.

Globally, the number of Hexadecanedioic acid manufacturers and exporters is concentrated in Germany, Switzerland and Japan following the increased incidence rates of the type 1 and Type 2 diabetes which is close to becoming a global epidemic. A niche application of Hexadecanedioic acid has been developed for the preparation of Insulin derivative – Insulin degludec. Therefore, Hexadecandioic acid acts as an important active pharmaceutical ingredient in the production of long-acting basal insulin degludec. Using Hexadecanedioic acid with a Glutamic acid spacer allows the formation of soluble and stable multi-hexamers at the B29 position near the –COOH end of C-peptide chain of Insulin. Another pharmaceutical application of Hexadecanedioic acid is in production of GLP-1 derivatives in a similar mechanism as Insulin derivatives. The addition of a dicarboxylic acid as lipophilic substituent modifies the cell communication in the glucose-dependent insulin production pathway and aids in the continuous release of Insulin. Hexadecanedioic acid is used an important constituent of pharmaceutical delivery of insulin analogs.

Current Research

Few research groups have attempted to study the antitumour activity of the esters of Hexadecanedioic acid, among which JE Petterson and Aas M. (1974) study is considered as the first proof. This 2-patient study conducted in 1974 concluded that this fatty acid is endogenously produced in the human liver during the synthesis of carnitine esters. The effect of this fatty acid is similar to that of palmitic acid, which is another unbranched long chain monocarboxylic fatty acid. The study pointed that hexadecanedioic acid is an intermediate in the anabolic pathway of hexadecanedioylcarnitine which is a storage fat and forms part of mitochondrial membranes. Significant studies on Hexadecanedioic acid between 2014 and 2017 focus on its effect on blood pressure regulatory pathways (PMID 28403188), the human gut mycobiome changes that induce obesity (PMID 26455903), B-Raf(V600E) cancer suppression by MAPK hyperactivation (PMID 26959890), and permeability transitioning in the human liver mitochondria and liposomes induced by ?, ?-dioic acids and Ca2+ (PMID 25217975).

References
  1. Oxygenation cascade in conversion of n-alkanes to ?, ?-dioic acids catalyzed by cytochrome P450 52A3, U Scheller, T Zimmer, D Becher, F Schauer… - Journal of Biological …, 1998 – ASBMB

Purified recombinant cytochrome P450 52A3 and the corresponding NADPH-cytochrome P450 reductase from the alkane-assimilating yeast Candida maltosa were reconstituted into an active alkane monooxygenase system. Besides the primary product, 1-hexadecanol, the conversion of hexadecane yielded up to five additional metabolites, which were identified by gas chromatography-electron impact mass spectrometry as hexadecanal, hexadecanoic acid, 1,16-hexadecanediol, 16-hydroxyhexadecanoic acid, and 1,16-hexadecanedioic acid. As shown by substrate binding studies, the final product 1,16-hexadecanedioic acid acts as a competitive inhibitor of n-alkane binding and may be important for the metabolic regulation of the P450 activity.

  1. Structural and metabolic requirements for activators of the peroxisome proliferator-activated receptor, M Göttlicher, A Demoz, D Svensson, P Tollet… - Biochemical …, 1993 - Elsevier

Fatty acids have recently been demonstrated to activate peroxisome proliferator-activated receptors (PPARs) but specific structural requirements of fatty acids to produce this response have not yet been determined. Importantly, it has hitherto not been possible to show specific binding of these compounds to PPAR. To test whether a common PPAR binding metabolite might be formed, we tested the effects of long-chain ?-3 polyunsaturated fatty acids, differentially ?-oxidizable fatty acids and inhibitors of fatty acid metabolism.

  1. Nanoridges that characterize the surface morphology of flowers require the synthesis of cutin polyester, Y Li-Beisson, M Pollard… - Proceedings of the …, 2009 - National Acad Sciences

Comparison of cutin monomer profiles in knockouts for CYP77A6 and the fatty acid ?-hydroxylase CYP86A4 provided genetic evidence that CYP77A6 is an in-chain hydroxylase acting subsequently to CYP86A4 in the synthesis of 10,16-dihydroxypalmitate. Biochemical activity of CYP77A6 was demonstrated by production of dihydroxypalmitates from 16-hydroxypalmitate, using CYP77A6-expressing yeast microsomes.

  1. Amino-Modified Diamond as a Durable Stationary Phase for Solid-Phase Extraction, G Saini, L Yang, ML Lee, A Dadson, MA Vail… - Analytical …, 2008 - ACS Publications

Solid-phase extraction was demonstrated using cholesterol, hexadecanedioic acid, and palmitoyloleoylphosphatidylcholine as analytes, and these results were compared to those obtained with commercially available materials. Breakthrough curves indicate that, as expected, porous diamond particles have higher analyte capacity than nonporous solid particles.

  1. The role of cytochrome P450 monooxygenases in microbial fatty acid metabolism, INA Van Bogaert, S Groeneboer, K Saerens… - The FEBS …, 2011 - Wiley Online Library

Bacteria and yeasts possess various P450 systems involved in alkane and fatty acid degradation, and often several enzymes with different activities and specificities are retrieved in one organism. Furthermore, P450s take part in the formation of fatty acid-based secondary metabolites. Finally, there are a substantial number of microbial P450s displaying activity towards fatty acids, but to which no biological role could be assigned despite the often quite intense research.

  1. New insights into the curing of epoxidized linseed oil with dicarboxylic acids, C Ding, PS Shuttleworth, S Makin, JH Clark… - Green …, 2015 - pubs.rsc.org

The effect of systematically increasing chain length of a series of linear ?,?-dicarboxylic acids (DCAs) from C6 to C18 diacids and a cyclic diacid, Pripol 1009F, on thermal and mechanical properties of the resultant epoxy thermosets derived from epoxidized linseed oil (ELO) are reported. Different techniques including differential scanning calorimetry (DSC), solvent extraction, FT-IR, NMR, dynamic mechanical analysis (DMA), tensile tests and thermogravimetric analysis (TGA) are used in this study. The results indicated that the obtained epoxy resins were highly crosslinked polymers with only a small fraction of low molecular weight soluble materials.

  1. Fatty acid?specific, regiospecific, and stereospecific hydroxylation by cytochrome P450 (CYP152B1) from Sphingomonas paucimobilis: Substrate structure required for ?-hydroxylation, I Matsunaga, T Sumimoto, A Ueda, E Kusunose… - Lipids, 2000 - Wiley Online Library

Fatty acid ?-hydroxylase from Sphingomonas paucimobilis is an unusual cytochrome P450 enzyme that hydroxylates the ?-carbon of fatty acids in the presence of H2O2. Herein, we describe our investigation concerning the utilization of various substrates and the optical configuration of the ?-hydroxyl product using a recombinant form of this enzyme. This enzyme can metabolize saturated fatty acids with carbon chain lengths of more than 10.

  1. Fatty acid activation of peroxisome proliferator-activated receptor (PPAR), C Bocos, M Göttlicher, K Gearing, C Banner… - The Journal of steroid …, 1995 - Elsevier

Peroxisome proliferators such as clofibric acid, nafenopin, and WY-14,643 have been shown to activate peroxisome proliferator-activated receptor (PPAR), a member of the steroid nuclear receptor superfamily. We have cloned the cDNA from rat that is homologous to that from mouse, which encodes a 97% similar protein.

  1. Simple syntheses of the polyamine alkaloid tenuilobine and analogues using selectively N-tritylated polyamines and dicarboxylic acids as bridging elements, S Vassis, I Govaris, K Voyagi, P Mamos… - Tetrahedron letters, 2002 - Elsevier

Selectively N-tritylated spermidine and spermine derivatives and the monophenacyl ester of 1,16-hexadecanedioic acid (Hda) were used to obtain the polyamine alkaloid tenuilobine and its fully reduced analogue. Other symmetric or side-chain-shortened tenuilobine analogues were readily obtained by using Hda or its dichloride or succinic anhydride to bridge the polyamine moieties.

  1. Production Of Alkanedioic Acids By Cytochrome P450Bm-3 Monooxygenase: Oxidation Of 16-Hydroxyhexadecanoic Acid To Hexadecane-1, 16-Dioic Acid, S Schneider, MG Wubbolts, D Sanglard… - Biocatalysis and …, 1999 - Taylor & Francis

Oxidation of 16-hydroxyhexadecanoic acid occurred with concomitant accumulation of small amounts of intermediates, one of which was tentatively identified as 16-dihydroxyhexadecanoic acid. Products of side reactions were 13.16-dihydroxy-hexadecanoic acid and 12, 16-dihydroxyhexadecanoic acid. The oxidation reactions did not take place in E. coli JM101 carrying the vector-DNA without the cyp102 gene.

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