Pomolic acid: A short review on its chemistry, plant sources, pharmacological properties, and patents

In this article, the chemistry, plant sources, pharmacological properties, and patents of pomolic acid (PA) are reviewed for the first time. Also known as benthamic acid, PA is a pentacyclic triterpenoid of the ursane type. Its chemical structure has a 30-carbon skeleton comprising five six-membered rings A–E with seven methyl groups and two hydroxyl groups. PA was first isolated from the peels of apples. The compound is commonly reported in species of the families Rosaceae and Lamiaceae. Anti-cancer activities represent the major pharmacological properties of PA with breast cancer and leukemia cells being most susceptible. A wide array of other pharmacological properties of PA have been reported. PA has two patents filed by the same group of scientists from the Federal University of Rio de Janeiro in Brazil. Some areas for further research on PA are suggested. Sources of information were from Google Scholar, PubMed, PubMed Central, Science Direct, J-Stage, and PubChem.

PA was chosen as the compound for review in this short article as there is none in the literature. Only some reviews on pentacyclic triterpenoids such as Salvador et al. (2012), Ghante andJamkhande (2019), andMioc et al. (2022) have included PA. Topics covered in this short review included chemistry, plant sources, synthesis, pharmacological properties, and patents. PA is reported in many plant species and is rich in bioactivities.

CHEMISTRY
PA or 3-β,19α-dihydroxy-urs-12-en-28-oic acid is a pentacyclic triterpenoid of the ursane type. PA is also known as benthamic acid (BA). It has a molecular formula of C 30 H 48 O 4 , and molecular weight of 473 g/mol. Its chemical structure has a 30-carbon skeleton comprising five six-membered rings A-E (Fig. 1).
PA has a carboxyl (-COOH) group at C17, and methyl (-CH 3 ) groups are attached to C4, C8, C10, C14, C19, and C20. C4 has two -CH 3 groups. There are four oxygen atoms, one at C3, two at C17, and one at C19. At C3, C17, and C19 are the hydroxyl (-OH) groups. Other triterpenoids of the ursane type include ursolic acid, asiatic acid, corosolic acid, and β-boswellic acid. Unlike PA which has -H at C2 and -OH group at C19, ursolic acid has -H at C2 and -H at C19 (Chan et al., 2019), and corosolic acid has -OH group at C2 and -H at C19 (Chan et al., 2022). The existence of -OH and -COOH groups in the PA molecule enables its intermolecular hydrogen bonding (Hou et al., 2022). The ability of PA to self-assemble via non-covalent interactions has been attributed to the presence of seven -CH 3 groups.
Although PA has been reported in many plant species, its content is very low. The content of PA in the roots and rhizomes of Potentilla species from Poland ranged from 0.09 mg/g in Potentilla reptans to 1.63 mg/g in Potentilla neumanniana (Jóźwiak et al., 2014). In China, the contents of PA in the fruits of different Chaenomeles species have been reported to range from 0.10% (Chaenomeles lagenaria) to 0.24% (Chaenomeles sinensis), 0.17% to 0.36% in C. sinensis from different prefectures, and 0.04% in the roots to 0.16% in the fruits of C. sinensis (Yang et al., 2009).
A practical approach to enhance the availability of PA is to synthesize PA from structurally similar compounds such as tormentic acid and euscaphic acid via regioselective acylation followed by Saito photochemical reduction (Kraft et al., 2019;Wiemann et al., 2016).
PA was identified as a potent inhibitor of SUMO-specific protease 1 (SENP1) with an IC 50 value of 5.1 μM (Wei et al., 2022). SENP1 is a member of the SENP family of proteins that can be used to detect bladder, colon, or prostate cancer in a biological sample (Uzoigwe et al., 2012). When combined with cisplatin, PA (IC 50 = 3.7 μM) exhibited potent inhibitory activity compared to cisplatin alone (IC 50 = 28 μM) against SK-OV-3 ovarian cancer cells.
The anti-cancer effects and molecular mechanisms of PA are listed in Table 2. They involved breast, lung, ovarian, and prostate cancer cells, including leukemia and glioma. Most susceptible are breast cancer and leukemia cells.
Against leukemia cells, anti-cancer effects include inhibition of cell growth, promotion of cell death, and induction of apoptosis. Molecular mechanisms against leukemia cells involve activation of the caspase pathway (caspases-3 and -9) and checking multidrug resistance (MDR) by over-expression of antiapoptotic Bcl-2 proteins.

Bioactivity Description of effect and mechanism involved Reference
Anti-HIV PA inhibited HIV-1 replication in acutely infected H9 cells with an EC50 value of 1.4 µg/ml. (Kashiwada et al., 1998) Anti-diabetic PA stimulated glucose uptake by 1.6-and 2.8-fold in basal and insulin-stimulated myotubes. (Lee and Thuong, 2010) Anti-fibrosis PA ameliorated fibroblast activation and renal interstitial fibrosis through inhibition of SMAD3-STAT3 signaling pathways. (Park et al., 2018) Anti-HPA PA strongly inhibited HPA induced by ADP and epinephrine with IC 50 values of 60 and 20 nM, respectively. (Estrada et al., 2009) PA was a competitive antagonist in the strong inhibition of HPA induced by ADP.

PATENTS
PA has two patents filed by the same group of scientists from the Federal University of Rio de Janeiro in Brazil (Gattass et al., 2004, 2008. The two patents are entitled, 'PA, its isomers, derivatives and their uses, pharmaceutical composition, method to prepare the pharmaceutical composition, and method for treating MDR tumors' and 'PA for treating MDR tumors'. The former (WO 2004/030682 A1) was a World Intellectual Property Organization (WIPO) Patent published in April 2004, while the latter (EP 1 549 330 B1) was a European Patent (EP) published in January 2008. The WIPO invention was specifically related to the identification of PA, its isomers, and derivatives as anti-neoplastic drugs, to be used in the treatment of patients suffering from tumors intrinsically MDR or tumors that acquired this resistance as a result of chemotherapy treatment (Gattass et al., 2004). The EP invention was related to the use of PA for the preparation of medicaments for the treatment of cancer with MDR (Gattass et al., 2008).

CONCLUSION
PA is an ursane-type pentacyclic triterpenoid. It is commonly reported in species of the families Rosaceae and Lamiaceae. Anti-cancer activities are the major pharmacological properties of PA with breast cancer and leukemia cells being most susceptible. A wide array of other pharmacological properties of PA have been reported. In view of the very low content of PA in plant species, more research on the synthesis of PA from structurally similar compounds is recommended to enhance its availability. The correlation of the bioactivities of PA with its structural properties, i.e., structure-activity relationship studies, is worthy of more indepth investigation. Analysis of the bioactivities and drug delivery of PA-gel holds great promise especially when its bioactivity is equal to or stronger than that of non-gel PA. Greater effort deserves to be accorded to strengthening the MDR potential of PA.

AUTHORS' CONTRIBUTIONS
All the authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revised it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; agreed to be accountable for all aspects of the work.

FUNDING
The authors are grateful to the Malaysian Ministry of Higher Education for the financial support of this publication (Grant No. FRGS/1/2022/STG04/UCSI/02/2).

CONFLICTS OF INTEREST
The authors report no financial or any other conflicts of interest in this work.

ETHICAL APPROVALS
This study does not involve experiments on animals or human subjects.

DATA AVAILABILITY
All data generated and analyzed are included in this research article.

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