Lactones are Cyclic Ester Moieties

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Lactones are cyclic ester moieties widely found in hormones, neurotransmitters, enzymes, plants, foods such as dairy, cosmetics, fragrances, and pharmacological drugs. The medicinal properties of lactones have been extensively investigated, initially through the isolation of natural, plant-based products. Lactone groups can be isolated from natural sources, such as the Asteraceae or Myristicaceae plant families, while synthetic lactones are derived from various reactions.

Although today’s pharmaceutical empire was established on botanic medicine, synthetic methods have become widely standardized (Shmidt, 2010). Continuous research displays a wide array of bioactive properties in synthetic lactones, such as anticancer/tumor, antioxidant, antimicrobial, anti-inflammatory properties, and even those that aid in cardiovascular disease. Lactones’ bioactivity has proven to be therapeutic for a multitude of diseases that thousands struggle with every day. The presence of these bioactive-rich properties truly makes synthetic lactones a promising compound for modern pharmaceuticals. This study reviews synthetic, bioactive lactones, along with their synthesis and biological mechanisms of action.

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The synthetic lactone compound, 1-isopropyl-2methylene-1,2 dihydrobenzochromen-3 one, or DL-3, has proven to be effective in inducing cell death via apoptosis. Furthermore, this compound suppresses the migration of hormone-independent and hormone-dependent breast cancerous cells, thus preventing metastasis. Although researchers have successfully isolated a complete series of twenty distinct alpha-methylene-gamma-lactones, the DL-3 compound is the most cytotoxic.

AD-013 increases the levels of expression for pro-apoptotic genes (caspases 3 and 9, BAX), while it decreases the anti-apoptotic genes (Bcl -2 and -xl). Furthermore, it increases the levels of p53. This series of actions results in a greater quantity of pro-apoptotic cells. The expression of cyclin CCNE1, CCND1, and CDK2 is increased. This hybrid compound lowers mRNA levels of p21, indicating that the cell cycle is not stopped at the G1/S phase. Approximately 80% of damage is initiated in DNA, and an inhibitory action is observed in 96% of the cells.

The synthesis of AD-013 is completed through a two-step reaction. The procedure involves TBD or Cs2CO3, the conjugate addition of ketones to 3-(diethoxyphosphoryl) coumarins, followed by the Horner Wadsworth Emmons methodology. This results in 3-diethoxyphosphoryl-4-(2-oxoalkyl)-3,4-dihydrocoumarins, along with formaldehyde. The lactone moieties are produced in single syn diastereoisomers.

Furthermore, studies display a parthenolide analogue capable of repressing prostatic cancer development. Parthenolide is a natural a-methylene-g-lactone, isolated from the Tanacetum parthenium plant. However, some drawbacks of a-methylene-g-lactones include high lipophilicity, which usually causes decreased bioavailability. In order to develop a lactonic moiety with improved bioavailability and solubility, derivatives of parthenolide were created via the diastereoselective adhesion of various 1o and 2o amines to the exocyclic double bond. This procedure established dimethylaminoparthenolide (DMAPT), an amino derivative of the original natural compound parthenolide. When DMAPT was formed into a salt, its solubility in water increased a thousand-fold compared to the natural compound parthenolide. Additionally, studies with rats show that DMAPT’s oral bioavailability is about 70%.

Lactones 4a and 4b were evaluated for their ability to initiate caspase-3 activity. Caspase-3 plays a major role in apoptosis. After exposing HL-60 cells to compounds 4a and 4b, it was indicated that the initiation of caspase-3 action started faster in the cells treated with the 4b compound than those treated with 4a. Furthermore, the BCL-2 gene is anti-apoptotic. Researchers found that the ratio of BCL-2 to b-actin amplicons decreased approximately two times in the leukemic cells exposed to the 4a compound. There was a decrease of approximately three times in cells exposed to 4b. These results suggest that both 4a and 4b compounds successfully inhibit the expression of the BCL-2 anti-apoptotic gene. While the BCL-2 anti-apoptotic gene’s expression is inhibited, the expression of BAX, a pro-apoptotic gene, remains unchanged. The effect of 4-methylideneisoxazolidin-5-ones was also tested on MRP1 and MDR1 genes. The products of MRP1 and MDR1 are proteins that are multidrug-resistant. These proteins are efflux pumps that pose a potent resistance against chemotherapeutic treatments. The overexpression of these genes in tumors plays a role in lowering the intracellular concentration of anti-cancer medications. This condition is known as multidrug resistance.

Lactone compounds 4a and 4b do not activate the expression of these malignant MRP1 and MDR1 pumps, which cause multidrug resistance. 4-methylideneisoxazolidin-5-ones also possess antimicrobial properties. The minimal inhibitory concentration was assessed for compounds 4a and 4b. Antibacterial bioactivity was evaluated using the bacterial strains of S. aureus, S. epidermidis, E. faecalis, E. coli, and P. aeruginosa. In order to assess the compounds’ potency against the fungal strain Candida albicans, the standard microdilution susceptibility test was used. The development of both S. aureus and S. epidermidis were inhibited by compound 4a with a concentration of 150 mg/ml. Compound 4b also inhibited both of these bacterial strains with a higher concentration of 300 mg/ml. 4a inhibited the growth of E. coli, however, 4b was unsuccessful at inhibiting growth—even with a concentration of 300 mg/ml. Neither of these compounds was successful at inhibiting P. aeruginosa. Additionally, the fungal strain C. albicans was completely inhibited by both 4a and 4b with a concentration of just 37.5 mg/ml. These results indicate that compounds 4a and 4b are potent antifungals, yet they are poor inhibitors of the evaluated Gram-positive and Gram-negative bacteria. To conclude, it is vital to note that lactones 4a and 4b are not rejected or eliminated by cells via membrane transporters.

A-methylene-g-lactones behave like alkylating agents, which is how their bioactivity is applied. In terms of synthesis, these moieties act as Michael type acceptors with binucleophiles, particularly with sulfhydryl functional groups of cysteine. Previous studies suggest that the anticancer bioactivity of these lactones is greatly correlated with their inhibitory action on various enzymes with thiols. These enzymes are active in the development and mechanism of proteins, ribonucleic acid, as well as deoxyribonucleic acid.

In this study, researchers successfully synthesized seco-A-pentacyclic triterpenoids-3,4-lactone groups for their antiviral activity against the Hepatitis B virus. Of these isolated compounds, particularly D7, inhibited HBeAg excretion with an IC50 of 0.14 mM, while D10 had a value of 0.86 mM. B4, D7, and D10 all effectively cleaved ring a 3,30 diolic acid, and indicated great inhibitory action on HBV DNA and cccDNA replication, respectively.

The synthesis of these compounds proceeds with C3 hydroxyl moieties of pentacyclic triterpenoids being oxidized into C3 ketones (a2-c2) via Jones reagent. Next, the Baeyer Villiger methodology is completed utilizing 3-chloroperbenzoic acid to produce the seco-a-3,4 lactone moieties: a3, b3, and c3. These are then converted into ring a cleaved 3, 28 diolic acids a4 and b4 via hydrolysis of lactones. Two intermediates, d3 and d6 of oleanic acid, were produced. Next, the seco-a triterpenoids D4 and 7 were produced using the Baeyer-Villiger oxidation on intermediates. To produce seco-a-3,4 lactones of oleanic acid, c12 and c13 double bonds were shielded primarily by bromine D8, and the process was later completed with oxidation D9 and deprotection. The target molecule d10 was produced, ending this reaction.


a-methylene-g-butyrolactone Bioactivity

Next, is a case where an a-methylene-g-butyrolactone moiety is introduced into 3-(4-hydroxyphenyl) propionic acid, creating a new compound that inhibits growth and initiates apoptosis in leukemic HL-60 cells. This newly synthesized compound suppresses the cancerous cells’ proliferative effects by inducing apoptosis, achieved via caspase-3 activation. Caspase-3 is activated by initiating cleavage of procaspase-3. As the compound achieves a high level of site specificity, healthy cells are less sensitive to it.

In terms of synthesis, 3-(4-hydroxyphenyl)propionic acid is extracted from Asplenium oropteris. Next, this acid is reduced using LiAlH4, forming compound two. The subsequent methylation of compound two results in a methyl ether in compound three. Compound three is oxidized using pyridinium chlorochromate, yielding an aldehyde. Reacting acetaldehyde with methyl acrylate and 1,4-diazabicyclo [2, 2, 2] octane creates moiety seven. Upon reaction of compound seven with N-bromosucinimide, stereoselectivity and regioselectivity are achieved. 2-carbomethoxyallylation of compound four with 2-carbomethoxyallylbromide, metallic tin, acetic acid, and p-toluenesulfonic acids produces the final product, compound nine. One can see how the anticancer/tumor bioactivity of sesquiterpene lactones is associated with the potential of a-methylene-g-lactone to bind to biological nucleophiles.

Bicyclic Lactone Bioactivity

Several synthetic lactones also contain antimicrobial bioactivity. Continuous investigation demonstrates that bicyclic lactones with three to four methyl groups are potent compounds that inhibit bacterial and fungal growth. After the synthesis of the newly formed bicyclic lactones, researchers identified the specific microorganisms targeted by their compounds. These bicyclic lactones were tested on various bacteria, fungi, and yeasts to identify potential inhibitory action.

Bio-assays were performed to accurately identify which strains of microorganisms are inhibited, and to measure the degree of inhibitory action. The tests were completed utilizing the bacterial strains E. coli, S. aureus, Bacillus subtilis B5, and P. fluorescens W1. The yeast strains utilized include Saccharomyces cerevisiae SV30, Candida albicans KL-1, and Yarrowia lipolytica ATCC 20460. Finally, the fungal strains used are Aspergillus niger XP, Alternaria sp., Penicillium sp., and Fusarium linii A3. The Bioscreen C system was used to perform the tests. Moreover, the test results consist of microbial growth curves of every strain tested. The curves are calculated using both incubation time and culture medium absorbency. In conclusion, the results show that unsaturated lactone 6a successfully inhibits the development of the bacterial strain P. fluorescens and the fungal strain F. linii. The unsaturated lactone compound 6b inhibited the growth of the yeast strains Y. lipolytica and C. albicans. Additionally, the following fungal strains: Alternaria sp., F. linii, and Penicillium sp. were also inhibited by 6b. The hydroxylactone compounds 7a, 7b, and 8a inhibited the growth of the bacterial strains B. subtilis and P. fluorescens. Particularly, the hydroxylactone 7b also inhibited S. aureus growth. However, these three hydroxylactones were not effective on yeast strains and many fungal strains. Exceptions to this result are hydroxylactones 7a and 7b, which did inhibit the development of the fungal strain F. linii. This study utilizes a unique synthesis known as biotransformation. Bicyclic lactones composed of three to four methyl moieties served as substrates for fungal-regulated biotransformation. This biotransformation reaction resulted in the creation of four new hydroxylactones. Isophrone was purchased and the ethyl esters were synthesized from the Claisen rearrangement reaction along with orthoacetate modifications. Hydrolysis of the esters 3a and 3b provided two acid diasteroisomers. Both bromolactones 5a and 6a were synthesized via dehydrodehalogenation.

Spironolactone is a well-known FDA approved medication, initially created in the 1950s. This drug is used for the treatment of primary hyperaldosteronism, congestive heart failure, liver cirrhosis with edema, nephrotic syndrome, hypertension, hypokalemia, and severe heart failure. Spironolactone’s structure contains an alpha-lactone moiety, which is responsible for this multi-targeted medication’s bioactivity.

Spironolactone behaves as an antagonist of aldosterone, a crucial steroid hormone. This drug acts by competitive binding of the receptors at the aldosterone-dependent sodium-potassium interchange locus within the kidney. Spironolactone causes larger quantities of water and sodium to be eliminated, while retaining potassium. Ultimately, this medication functions as an antihypertensive and as a diuretic drug through this mechanism of action. There are large quantities of aldosterone in hyperaldosteronism. When Spironolactone competes with the aldosterone hormone for receptor sites, therapeutic activity is realized against ascites and edema. This drug effectively blocks secondary aldosteronism initiated by a decrease in volume as well as the associated sodium decrease that results from diuretic therapies. It should be noted that the prolonged use of Spironolactone is not recommended due to the potential occurrence of menstrual irregularities, dehydration, hyperkalemia, among other serious side effects. Spironolactone undergoes retrosynthetic analysis and its synthesis is achieved by the intramolecular esterification reaction.

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In this study, researchers synthesized derivatives from the sesquiterpene lactones (SL’s), a-Santonin and Sclareolide. Upon securing their derivatives, they evaluated their anti-inflammatory bioactivity. Furthermore, they also assessed the activity of the lactone moiety in the SL derivatives. The analogues were synthesized from a-Santonin and Sclareolide. a-Santonin is isolated from the Artemisia family, while Sclareolide can be isolated from the Salvia family and other plants. Since SL’s such as a-Santonin and Sclareolide have been utilized to reduce and alleviate inflammation for centuries, the analogues of these SL’s were tested for any increased bioactivity.

Compound FP6 has been the most successful at reducing inflammation. Results indicate that indeed one SL derivative successfully regulated PGE2 levels via the reduction of cyclooxygenase-2 activity, thus reducing inflammation. PGE2 is a specific type of prostaglandin, these result in an increased sense of pain as well as inflammation. COX or cyclooxygenase enzymes play a critical role in transforming arachidonic acid into prostaglandins. Out of all the synthesized derivatives, particularly compound FP6 exhibited the highest binding affinity to both Ser530 and Tyr385 on the docking assessment. Moreover, biological assays revealed that compound FP6 was able to inhibit COX. Not only was there confirmed inhibitory action on COX, but the synthetic derivative also displayed greater inhibition than its natural origin: a-Santonin. Finally, 19F NMR showed that compound FP6 contains a CF3 group, a moiety responsible for providing flexibility and stability. Interestingly, this group is also present in the well-known marketed nonsteroidal anti-inflammatory drug celecoxib. In order to synthesize compound FP6, an oximation of a-Santonin was performed in which santoninoxime reacted with alkyl bromide.

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Lactones are Cyclic Ester Moieties. (2019, Dec 24). Retrieved from