Application research of octadecanedioic acid

Introduction

Octadecanedioic acid (also known as 1,18-Octadecanedioic Acid; Figure 1) is a key component of Novo Nordisk’s semaglutide (Ozempic and Rybelsus), an antidiabetic medication that is administered once weekly as a result of superior HSA engagement compared to standard lipidation strategies wherein the single carboxylic acid functionality is used to conjugate the therapeutic agent (e.g.,liraglutide, requiring once-daily administration).[1]

Synthesis of Octadecanedioic acid

Possible diacid monomers with longer alkyl chains(more than 12 carbons) are rarely found in nature and hence are mostly synthesized using C─C coupling reactions of petroleum-based compounds, which detracts from the goal of biomass-based polyester production. Recent advances in catalytic conversions of plant oils have made biomass-containing diacids much more accessible. A joint venture between Wilmar International and Elevance Renewable Sciences has been able to convert biomass palm oil into octadecanedioic acid (OA) (diacid with 18 carbons) on a commercial scale. Oleic acid, which is abundantly found in palm oil, is used to yield fully (100%) biomassbased octadecanedioic acid via olefin metathesis and hydrogenation (Scheme 1). Green color shows biomass-based components and black color shows petroleum-based components. Biomass-based oleic acid reacts with petroleum-based 1-butene to form dec-9-enoic acid and dodec-3-ene. Two molecules of dec-9-enoicacid undergo another round of olefin metathesis to form octadec-9-enedioic acid and ethene. Further hydrogenation of octadec-9-enedioic acid forms octadecanedioic acid, which is 100% biomass-based as no part of the initially used 1-butene is incorporated in octadecanedioic acid.[2]

Application of octadecanedioic acid

Biomass-based linear aliphatic polyesters Synthesis

A series of biomass-based linear aliphatic polyesters are synthesized by combining sebacic acid (SA) (C10 diacid) and 1,18-octadecanedioic acid (OA) (C18 diacid) with a series of diols with varied alkyl chain lengths (C2 to C10 diols). SA and OA are obtainable from castor oil and palm oil, respectively. The reaction extent (polymerization extent) is high (≥96%) in all cases, and the number-average molecular weight (Mn) is 10 000-43 000 g mol-1 after purification. A possible limitation of currently available biomass-derived polyesters is their relatively low melting temperatures (Tm). The polyesters synthesized using OA with a long alkyl chain (C18 chain) in the present work exhibit relatively high Tm values of 78-93 °C, which are rather close to that (105-118 °C) of low-density polyethylene (LDPE), and may serve as biomass-based alternatives to LDPE with respect to thermal properties. Scientifically notably, an odd-even effect is observed in the Tm values. Polyesters with an even total-number of carbon atoms in the repeating unit have higher Tm values than their odd total-number counterparts likely due to their different orientations of dipoles of the polar ester groups along the backbone chain.[2]

Octadecanedioic Acid-Paclitaxel Complexed Synthesis

In this study,Callmann et al. describe the design, synthesis, and antitumor activity of an 18 carbon α,ω-dicarboxylic acid monoconjugated via an ester linkage to paclitaxel (PTX). This 1,18-octadecanedioic acid-PTX (ODDA-PTX) prodrug readily forms a noncovalent complex with human serum albumin (HSA). Preservation of the terminal carboxylic acid moiety on ODDA-PTX enables binding to HSA in the same manner as native long-chain fatty acids (LCFAs), within hydrophobic pockets, maintaining favorable electrostatic contacts between the ω-carboxylate of ODDA-PTX and positively charged amino acid residues of the protein. This carrier strategy for small molecule drugs is based on naturally evolved interactions between LCFAs and HSA, demonstrated here for PTX. ODDA-PTX shows differentiated pharmacokinetics, higher maximum tolerated doses and increased efficacy in vivo in multiple subcutaneous murine xenograft models of human cancer, as compared to two FDA-approved clinical formulations, Cremophor EL-formulated paclitaxel (crPTX) and Abraxane (nanoparticle albumin-bound (nab)-paclitaxel).[3]

Octadecanedioic Acid-Terlipressin Conjugate Synthesis

Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease first reported over a century ago, but its management still poses an unmet challenge. A therapeutic agent found to stabilize the condition is a short cyclic peptide, vasopressin analogue, terlipressin (TP). While TP is commonly prescribed for HRS patients in most parts of the world, it was only recently approved for use in the United States. TP exhibits short circulation half-lives and adverse side effects associated with the dose required. Herein, Berger et al. present a 1,18-octadecanedioic acid (ODDA) conjugate of the cyclic peptide (ODDA-TP), which enables noncovalent binding to serum albumin via native fatty acid binding modes. ODDA-TP is demonstrated to outperform TP alone in studies including in vitro cellular receptor activation, stability in plasma, pharmacokinetics, and performance in vivo in rats. Specifically, ODDA-TP had an elimination half-life 20 times that of TP alone while exhibiting a superior safety profile.[1]

Used as the material biomarker for MI-induced sensitization of acupoints

A total of 20 New Zealand rabbits were randomly and equally divided into a control group and a model group. The MI model was established by occlusion of the anterior descending branch of the left coronary artery with a controllable air balloon inflation method for 5 min/time, twice a day (4-hours' interval) for continuous 5 days (the first stage of MI). After one day's rest, another 5 days' occlusion was conducted again (the second stage of MI) in the same way. The rabbits of the control group were treated with the same procedures but without occlusion. Subcutaneous microdialysis fluid samples were collected from "Neiguan" (PC 6), "Shenmen" (HT 7), "Xinshu" (BL 15), and "Taixi" (KI 3) regions on day 8(after recovery from operation), 14 (the first stage of MI), and 20 (the second stage of MI), as well as collected from PC 6 region during and post-acupuncture stimulation of PC 6, respectively. Manual acupuncture stimulation was applied to the right PC 6 for 30 min. Partial least squares -linear discriminant analysis (PLS-DA) was used to identify different metabolism patterns of the microdialysis fluid sample between groups and at different time-points in the same one group, and the distinct metabolites as the potential markers between groups were weighted via the values of variable importance in the projection (VIP) in combination with t-test analysis. An area under the curve (AUC) >1.0 indicated a test exhibiting good discrimination between groups. RESULTS: Six metabolites identified to be significantly different between the control and model groups were L-glutamic acid, phenylalanine and 3-hydroxyisobutyric acid (which were significantly increased relevant to the control group), and L-histidine, octadecanedioic acid and 9-keto palmitic acid (significantly decreased relevant to the control group) in the microdialysate of PC 6, HT 7 and BL 15 regions. In the microdialysate of PC 6, 4 metabolites including L-glutamic acid, octadecanedioic acid and 8-isohydroxy PGF 2 α (significantly increased), as well as L-histidine (markedly decreased) were identified to be considerably different between the model and control groups. After acupuncture for 30 min, the AUC level of L-glutamic acid was further significantly increased ( P<0.05), that of L-histidine obviously decreased, and those of octadecanedioic acid and 8-isohydroxy PGF 2 α turned back nearly to the level of pre-MI. CONCLUSION: L-glutamic acid, phenylalanine, 3-hydroxyisobutyric acid, L-histidine, octadecanedioic acid and 9-keto palmitic acid from PC 6, HT 7 and BL 15 regions may be used as the material biomarker for MI-induced sensitization of these acupoints. Manual acupuncture intervention of PC 6 induces a significant change of L-histidine and L-glutamic acid in the local subcutaneous tissues.[4]

References

1. Berger O, Choi W, Ko CH, et al. Long-Circulating Vasoactive 1,18-Octadecanedioic Acid-Terlipressin Conjugate. ACS Pharmacol Transl Sci. 2024;7(5):1252-1261. Published 2024 Apr 30. doi:10.1021/acsptsci.3c00305

2. Loh JWJ, Chua NH, Goto A. Synthesis of Biomass-Based Linear Aliphatic Polyesters Based on Sebacic Acid and 1,18-Octadecanedioic Acid and Their Thermal Properties and Odd-Even Effect. Macromol Rapid Commun. 2025;46(6):e2400941. doi:10.1002/marc.202400941

Application research of octadecanedioic acid

3. Callmann CE, LeGuyader CLM, Burton ST, et al. Antitumor Activity of 1,18-Octadecanedioic Acid-Paclitaxel Complexed with Human Serum Albumin. J Am Chem Soc. 2019;141(30):11765-11769. doi:10.1021/jacs.9b04272

4. Xing BB, Huang M, Zhang D, Ding GH. Zhen Ci Yan Jiu. 2018;43(7):433-439. doi:10.13702/j.1000-0607.180066