SYNTHESIS OF COCRYSTALS OF BETULIN WITH SUBERIC ACID AND STUDY OF THEIR PROPERTIES

Lupane triterpenoids, betulin and its derivatives, are attracting great interest due to their wide range of biological and pharmacological activities. However, the poor solubility of betulin and its derivatives in aqueous media significantly reduces their bioavailability. Obtaining cocrystals, that is, multicomponent crystal systems containing active pharmaceutical ingredients and non-toxic partner molecules in their structure, is used in pharmacy to change the physicochemical properties of drugs, including the rate of dissolution and solubility. In this study, cocrystals of betulin with suberic acid were obtained by liquid-assisted grinding method using organic solvents of different polarity: ethanol, acetone, ethyl acetate, chloroform, toluene, dioxane. The formation of cocrystals was confirmed by X-ray diffraction analysis, IR spectroscopy, and thermal analysis. It has been shown that cocrystals of betulin with suberic acid contain water molecules in their structure; anhydrous cocrystals can be obtained by heating a physical mixture of reagents until the acid melts. The results of experiments on the dissolution of cocrystals of betulin with suberic acid in comparison with the data for cocrystals of betulin with adipic acid showed that an increase in the length of the aliphatic acid chain leads to a decrease in the rate of betulin release into solution.

Eutectic Formation of Naproxen with Some Dicarboxylic Acids

Eutectic formation with additives is one of the established methods to improve the dissolution behaviors of active pharmaceutic ingredients (APIs). The improvement is mainly due to the increase in the surface area for dissolution, which originates from the finely divided micro-domains generated through the phase separation of the miscible liquid components upon solidification. The present study is to identify eutectic-forming additives for naproxen (NPX), a class II API of the biopharmaceutical classification system. A particular aim was to develop a eutectic mixture with NPX at least over 20 wt%, a minimum to be practical for oral delivery. Screening based on the proximity of the solubility parameter values identified dicarboxylic acids (succinic acid, glutaric acid, and suberic acid) as desirable additives for NPX. Binary melting diagrams were constructed to confirm the eutectic compositions, and the eutectic mixture with suberic acid (NPX 55 wt%) was further investigated. The dissolution (at pH 5.0) of the melt crystallized eutectics was enhanced compared to the simple physical mixture of the same compositions and neat NPX, which was attributed to the microscopically observed lamellar structures. The current study should support the systematic investigations of API eutectic mixtures by selecting appropriate eutectic-forming additives.

Сocrystals of betulin with suberic acid: mechanochemical synthesis and thermal behavior

In this work, the cocrystals of betulin with suberic acid were prepared by liquid-assisted grinding method using solvents of different polarity. The formation of cocrystals was confirmed by means of powder X-ray diffraction, IR spectroscopy and thermal analysis. It was shown that under heating, a structural transformation occurred after water removal, followed by cocrystal dissociation.

Novel tri-[2]rotaxane-based stimuli-responsive fluorescent nanoparticles and their guest controlled reversible morphological transformation properties

Novel tri-[2]rotaxane-based fluorescent nanomaterials show selective fluorescence response towards suberic acid and could reversibly switch from nanoparticles to nano-film.

Dietary Suberic Acid Protects Against UVB-Induced Skin Photoaging in Hairless Mice

Ultraviolet (UV) radiation is a major cause of skin photoaging, which is mainly characterized by dryness and wrinkle formation. In the current study, we investigated the anti-photoaging effects of dietary suberic acid, a naturally occurring photochemical, using UVB-irradiated hairless mice. Mice were exposed to UVB three times weekly and fed diets containing three different suberic acid concentrations (0.05%, 0.1% and 0.2%) for 10 weeks. It was found that suberic acid inhibited UVB-induced skin dryness, wrinkle formation, and epidermal thickness in hairless mice. In parallel with phenotypic changes, suberic acid attenuated UVB-induced matrix metalloproteinase (MMP) genes (MMP1a, MMP1b, MMP3, and MMP9), while accelerating collagen genes including collagen type I alpha 1 chain (COL1A1), COL1A2, and COL3A1 and hyaluronic acid synthases genes (HAS1, HAS2 and HAS3). We further demonstrated that suberic acid upregulated the molecules involved in the transforming growth factor–β (TGF-β)/SMAD pathway, but downregulated the molecules participating in the mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) signaling in UVB-irritated hairless mice. Collectively, we propose that suberic acid may be a promising agent for treating skin photoaging.

Preoperative plasma fatty acid metabolites inform risk of prostate cancer progression and may be used for personalized patient stratification

Background Little is known about the relationship between the metabolite profile of plasma from pre-operative prostate cancer (PCa) patients and the risk of PCa progression. In this study we investigated the association between pre-operative plasma metabolites and risk of biochemical-, local- and metastatic-recurrence, with the aim of improving patient stratification. Methods We conducted a case-control study within a cohort of PCa patients recruited between 1996 and 2015. The age-matched primary cases (n = 33) were stratified in low risk, high risk without progression and high risk with progression as defined by the National Comprehensive Cancer Network. These samples were compared to metastatic (n = 9) and healthy controls (n = 10). The pre-operative plasma from primary cases and the plasma from metastatic patients and controls were assessed with untargeted metabolomics by LC-MS. The association between risk of progression and metabolite abundance was calculated using multivariate Cox proportional-hazard regression and the relationship between metabolites and outcome was calculated using median cut-off normalized values of metabolite abundance by Log-Rank test using the Kaplan Meier method. Results Medium-chain acylcarnitines (C6-C12) were positively associated with the risk of PSA progression (p = 0.036, median cut-off) while long-chain acylcarnitines (C14-C16) were inversely associated with local (p = 0.034) and bone progression (p = 0.0033). In primary cases, medium-chain acylcarnitines were positively associated with suberic acid, which also correlated with the risk of PSA progression (p = 0.032, Log-Rank test). In the metastatic samples, this effect was consistent for hexanoylcarnitine, L.octanoylcarnitine and decanoylcarnitine. Medium-chain acylcarnitines and suberic acid displayed the same inverse association with tryptophan, while indoleacetic acid, a breakdown product of tryptophan metabolism was strongly associated with PSA (p = 0.0081, Log-Rank test) and lymph node progression (p = 0.025, Log-Rank test). These data were consistent with the increased expression of indoleamine 2,3 dioxygenase (IDO1) in metastatic versus primary samples (p = 0.014). Finally, functional experiments revealed a synergistic effect of long chain fatty acids in combination with dihydrotestosterone administration on the transcription of androgen responsive genes. Conclusions This study strengthens the emerging link between fatty acid metabolism and PCa progression and suggests that measuring levels of medium- and long-chain acylcarnitines in pre-operative patient plasma may provide a basis for improving patient stratification.

Synthesis of 2-aminosuberic acid derivatives as components of some histone deacetylase inhibiting cyclic tetrapeptides

A new synthesis of the important amino acid 2-aminosuberic acid from aspartic acid is reported. The methodology involves the alternate preparation of (S)-2-aminohept-6-enoate ester as a building block and its diversification through a cross-metathesis reaction to prepare the title compounds. The utility of the protocol is demonstrated through the preparation of three suberic acid derivatives of relevance to the design and the synthesis of peptides of biological relevance.