Lactones are Cyclic Ester Moieties
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 extendedly investigated initially through isolation of natural plant-based products. Lactone groups may be isolated from natural sources such as the Asteraceae or Myristicaceae plant families, while synthetic lactones are derived from diversified reactions.
Even though today’s pharmaceutical empire was established from botanic medicine, synthetic methods have become widely standard (Shmidt, 2010). Continuous research displays a wide array of bioactive properties in synthetic lactones such as anticancer/tumor, antioxidant, antimicrobial, anti-inflammatory, and even aids in cardiovascular disease. Lactones’ bioactivity has proven to be therapeutic to 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 mechanism of action.
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 a-methylene-d-lactones, the DL-3 compound is the most cytotoxic.
The mechanism of action is as follows, in breast cancer apoptosis is controlled by two factors: the Bcl-2 gene proteins as well as the Bax gene. The BCL-2 gene is responsible for preventing apoptosis, while the Bax gene induces apoptosis. The anti-apoptic BCL-2 gene behaves as an antagonist and will therefore inhibit the Bax apoptic inducing gene. Inhibition of the BCL-2 gene and/or the increase in Bax expression creates an imbalance leading to apoptic cell death. Cells with the DL-3 lactone indeed displayed a heightened ratio of the Bax and BCL-2 genes. This result suggests that cancer cell apoptosis is controlled by the mitochondrial pathway. Effectively, 1-isopropyl-2-methylene-1,2 dihydrobenzochromen-3 one (DL-3) greatly lowered levels of BCL-2 expression and protein levels, while increasing Bax expression. In terms of metastasis, migration of cancerous cells is regulated by the extracellular matrix. There are a variety of highly specialized enzymes categorized as proteases which degrade proteins and peptides. Proteases such as uPA and MMP’s have a significant role in breaking down the extracellular matrix. In a patient with cancer, there is an increased production and activity of these proteases in tumor cells. A decrease in protease levels in protein and mRNA levels displays how the DL-3 lactone compound strongly inhibits these specialized proteases. One disadvantage to this DL-3 compound is that it will also attack normal, healthy cells. Due to this drawback, DL-3 cannot yet be considered a finalized therapeutic compound. Further research of a-methylene-d-lactones such as increasing selectivity and site specificity is crucial. Still, DL-3 or 1-isopropyl-2-methylene-1,2 dihydrobenzochromen-3 one provides great insight into additional development and sophistication of anticancer synthetic compounds. The synthesis of the DL-3 compound was performed via the Horner Wadsworth Emmons olefination methodology. This reaction successfully introduced the d lactone with the methylene functional group.
The anti-cancer bioactivity of a-methylene-d-lactones are again confirmed when this moiety is introduced into a coumarin derivative. Coumarin a natural compound, does not possess therapeutic activity on its own. However, various synthetic analogous of coumarin have displayed anti-cancer bioactivity. Therefore, a hybrid molecule known as AD-013 or (R*)-8-methoxy-3-methylene-4-[(S*)-2oxocyclohexyl]chroman-2-one composed of a coumarin derivative and an a-methylene-d-lactone moiety was synthesized. This allowed for the study of possible anti-proliferative activity in the breast cancer cell line known as MCF-7. The biological assays indicate that this hybrid compound posed inhibitory activity upon BRCA1 (breast cancer gene 1) and lowered the activity of its proteins. Also, this compound aided in repairing impaired DNA. Exposing cancerous MCF-7 cells to the AD-013 compound lowered the expression of various repair genes.
AD-013 increases the levels of expression for pro apoptotic genes (caspases 3 and 9, BAX), while decreased the anti-apoptotic genes (Bcl -2 and -xl). Furthermore, it increased the levels of p53. This series of action result in a greater quantity of pro apoptotic cells. Cyclin expression of CCNE1, CCND1, and CDK2 was increased. This hybrid compound lowers mRNA levels of p21. This displays how that the cell cycle was not stopped at the G1/S phase. Approximately 80% of damage was initiated in DNA, and inhibitory action is observed in 96% of the cells.
Synthesis of AD-013 was completed through a two step reaction. The procedure involves TBD or Cs2CO3, the conjugate addition of ketones to 3-(diethoxyphosphoryl) coumarins, next follows the Horner Wadsworth Emmons methodology. This results in 3-diethoxyphosphoryl-4-(2-oxoalkyl)-3,4-dihydrocoumarins along with formaldehyde. The lactone moieties were 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, there was a thousand-fold increased solubility in water in comparison to the natural compound parthenolide. Additionally, studies with rats portray that DMAPT’s oral bioavailability is of about 70%.
Researchers became interested in dimethylaminoparthenolide (DMAPT) due to its anti-cancer bioactivity. More specifically, studies completed with mice indicate how DMAPT might possess bioactivity in males with prostate cancer that is resistant to castration. DMAPT’s mechanism of action to selectively kill prostate cancer cells involves the generation of ROS (Reactive Oxygen Species) and JNK (c-jun N-terminal kinase) activation, suppression of NFkB DNA binding, and lastly, the expression of NFkB mediated anti-apoptosis proteins. More specifically, a cells red-ox potential changes upon a decrease in thiol concentration. This results in oxidative stress, which creates ROS. Reactive oxygen species begins programmed cellular death through the mitochondrial dependent pathway. Furthermore, JNK activation induces apoptosis. According to leading researchers, the weaker the cancerous cell becomes, the lower the cells’ glutathione levels. In prostate cancer, there is increased expression of the NFkB transcription factor. DMAPT removes the cancerous cells’ defenses provided to it by the NFkB transcription factor. DMAPT effectively deteriorates NFkB by prohibiting its DNA binding ability, this destroys the transcription factor’s ability to express anti-apoptic proteins. A variety of distinct a-methylene-g-lactones are able to suppress NFkB, while simultaneously inducing apoptotic activity of p53 protein. Finally, DMAPT has in vivo activity using mice to test its therapeutic effect on lung and bladder cancers. Both lung and bladder cancers indicate repression of tumors after DMAPT was administered orally.
a-methylene-g-lactones have also been studied for their anti-leukemic bioactivity. The following experiment focused on evaluating the cytotoxic activity of 4-methylideneisoxazolidin-5-ones against leukemic HL-60 cells. 4-methylideneisoxazolidin-5-ones are a specific class of a-methylene-g-lactones.
Lactones 4a and 4b were evaluated for the ability to initiate caspase-3 activity. Caspase-3 plays a major role in apoptosis. After exposing HL-60 cells to compounds 4a and 4b, results indicated that initiation of caspase-3 action started faster in the cells treated with 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 and 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 is not changed. The effect of 4-methylideneisoxazolidin-5-ones was also tested on MRP1 and MDR1 genes. The products of MRP1 and MDR1 are proteins which are multidrug resistant. These proteins are efflux pumps that pose powerful resistance against chemotherapeutic treatments. The over expression of these genes in tumorous possesses a role in lowering the intracellular concentration of anti-cancer medications. This case 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. Development of both S. aureus and S. epidermidis was 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 growth of E. coli, however 4b was unsuccessful at inhibiting growth even with a concentration of 300mg/ml. Neither of these two compounds were 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 display that compounds 4a and 4b are potent antifungals, while they are poor inhibitors of the evaluated gram positive and gram negative bacteria. To conclude, it is essential 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, this 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 anti-viral activity of the Hepatitis B virus. Of these isolated compounds particularly D7 inhibitted HBeAg excretion with an IC50 of 0.14 mM, while D10 had a value of 0.86 mM. B4, D7, and D10 all effectively ring-a cleaved 3,30 diolic acid, and indicated great inhibitory action of 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 Bayer Villiger methodology is completed utilizing 3 chloroperbenzoid 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 Villager oxidation on intermediates. To produced seco-a-3,4 lactones of oleanic acid, c-12 and c-13 double was shielded primarily by bromine d8, and later finished with oxidization d9 and deprotection, the target molecule d10 was produced ending this reaction.
Next, is a case in which an a-methylene-g-butyrolactone moiety is introduced into 3-(4-hydroxyphenyl) propionic acid to create a new compound that prohibits growth and initiates apoptosis in leukemic HL-60 cells. The newly synthesized compound suppresses the cancerous cells’ proliferative effect by inducing apoptosis. Apoptosis is accomplished through caspase-3 activation. Capase-3 is activated by initiating cleavage of procaspase-3. This compound achieves a high level of site specificity, therefore healthy cells are less sensitive to it.
In terms of synthesis, 3-(4-hydroxyphenyl)propionic acid is isolated from Asplenium oropteris. Next, this acid is reduced using LiAlH4, creating compound two. Once compound two is methylated, a methyl ether is afforded in compound three. Compound three is oxidized using pyridinium chlorochromate, thus producing an aldehyde. Reacting acetaldehyde with methyl acrylate, and 1,4-diazabicyclol [2, 2, 2,] octane produced moiety seven. The reaction of compound seven with N-bromosucinimide created stereo and regioselectivity. 2-carbomethoxyallylation of compound four with 2-carbomethoxyallylbromide, along with metallic tin, acetic acid, and p-toluenesulfonic acids produces the final product: compound nine. One can see how the anti-cancer/tumor bioactivity of sesquiterpene lactones is associated with a-methylene-g-lactone’s potential to bind biological nucleophiles.
Bicyclic Lactone Bioactivity
Several synthetic lactones also contain antimicrobial bioactivity. Continuous investigation displays that bicyclic lactones with three to four methyl groups are powerful compounds that inhibit bacterial and fungal development. After synthesis of the newly formed bicyclic lactones, researchers identified which specific microorganisms their compounds targeted. These bicyclic lactones were tested on diversified 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 its 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 are as follows: 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 tests. Furthermore, 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 display that unsaturated lactone 6a successfully inhibit the development of the bacterial strain P. fluorescens and that of the fungal strain F. linii. The unsaturated lactone compound 6b, inhibited the development of the yeast strains Y. lipolytica as well as C. albicans. In addition, the following fungal strains were also inhibited by 6b: Alternaria sp., F. linii, and lastly Penicillium sp. The hydroxylactone compounds 7a, 7b, and 8a inhibited the development of the bacterial strains: B. subtillis and P. fluorescens. Particularly the hydroxylactone 7b also inhibited S. aureus growth. However, these three hydroxylactones were not active on yeast strains and many fungal strains. The exception to this result are hydroxylactones 7a and 7b, which did inhibit development of the fungal strains F. linii. This study utilizes a distinct synthesis known as biotransformation. Bycyclic lactones composed of three to four methyl moieties behaved as substrates for fungal regulated biotransformation. From this biotransformation reaction a series of four hydroxylactones were created as the end product. Isophrone was purchased. The ethyl esters were synthesized from the Claisen rearrangement reaction along with orthoacetate alterations. Hydrolysis of the esters 3a and b 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 1950’s. This drug is used for the treatment of primary hyperaldosteronism, congestive heart failure, liver cirrhosis with edemas, nephrotic syndrome, hypertension, hypokalemia, and severe heart failure. Spironolactone’s structure contains an ?-lactone moiety 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 greater quantities of water and sodium to be eliminated, while retaining potassium. Ultimately, this medication behaves as an antihypertensive and as a diuretic drug through this mechanism of action. There are great amounts of aldosterone in hyperaldosteronism. When Spironolactone competes with the aldosterone hormone for receptor sites, therapeutic activity is offered 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 extended use of Spironolactone is not recommended due to the possibility of menstrual irregularities, dehydration, hyperkaliemia, amongst other serious side effects. Spironolactone undergoes retrosynthetic analysis. Spironolactone undergoes its synthesis by intramolecular esterification reaction.
In this study researchers synthesized derivatives from the sesquiterpene lactones (SL’s) a-Santonin and Sclareolide. Upon obtaining their derivatives, they assessed their anti-inflammatory bioactivity, furthermore the activity of the lactone moiety was evaluated 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 as well as other plants. Because SL’s such a-Santonin and Sclareolide have been utilized to reduce and alleviate inflammation for centuries, the analogues of these SL’s were assessed to test 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 cyclo oxygenase 2 activity, thus reducing inflammation. PGE2 is a specific type of prostaglandin, these result in the increased sense of pain as well as inflammation. COX or cyclo oxygenase enzymes play an essential role in transforming arachidonic acid into prostaglandins. Out of all of the synthesized derivatives, particularly compound FP6 exhibited the greatest binding affinity to both Ser530 and Tyr 385 on the docking assessment. Furthermore, biological assays revealed that compound FP6 was able to inhibit COX. Not only was there confirmed inhibitory action of COX, but the synthetic derivative also displayed greater inhibition than its natural origin: a-Santonin. Finally, 19F NMR revealed 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.