Selected Plant Triterpenoids and Their Derivatives as Antiviral Agents.

The results of the most recent investigation of triterpenoid-based antiviral agents namely in the HIV-1 and HSV-1 treatment were reviewed and summarized. Several key historical achievements are included to stress consequences and continuity in this research. Most of the agents studied belong to a series of compounds derived from betulin or betulinic acid, and their synthetic derivative is called bevirimat. A termination of clinical trials of bevirimat in Phase IIb initiated a search for more successful compounds partly derived from bevirimat or designed independently of bevirimat structure. Surprisingly, a majority of bevirimat mimics are derivatives of betulinic acid, while other plant triterpenoids, such as ursolic acid, oleanolic acid, glycyrrhetinic acid, or other miscellaneous triterpenoids, are relatively rarely involved in a search for a novel antiviral agent. Therefore, this review article is divided into three parts based on the leading triterpenoid core structure.

Hierarchical peroxiredoxin assembly through orthogonal pH-response and electrostatic interactions.

Morpheeins are proteins that adapt their morphology and function to the environment. Therefore, their use in nanotechnology opens up the bottom-up preparation of anisotropic metamaterials, based on the sequential use of different stimuli. A prominent member of this family of proteins is peroxiredoxins (Prx), with dual peroxidase and chaperone function, depending on the pH of the media. At high pH, they show a toroidal morphology that turns into tubular stacks upon acidification. While the toroidal conformers have been explored as building blocks to yield 1D and 2D structures, the obtention of higher ordered materials remain unexplored. In this research, the morpheein behaviour of Prx is exploited to yield columnar aggregates, that are subsequently self-assembled into 3D anisotropic bundles. This is achieved by electrostatic recognition between the negatively charged protein rim and a positively charged porphyrin acting as molecular glue. The subsequent and orthogonal input lead to the alignment of the monodimensional stacks side-by-side, leading to the precise assembly of this anisotropic materials.

Nano-assembly of cytotoxic amides of moronic and morolic acid.

Moronic acid and morolic acid, less frequently studied plant triterpenoids, were subjected to derivation with several structural modifiers, namely, piperazine-, pyrazine-, 1H-indole- and L-methionine-based compounds. Derivation was targeted to design and prepare novel compounds capable of nano-assembling and/or displaying cytotoxicity. Formation of nanostructures has been proven for several novel target compounds that formed different types of nanostructures, either in chloroform or in water. Isometric nanoparticles with broad size distributions (12 and 25), distorted single sheets (23) or very large thin warped films (13) were formed in chloroform solutions. Sheet-like nanostructures (12 and 23), and sphere-like nanostructures (hydrogen bonding connected nanoparticles; 3, 5, 13, 21 and 25) were formed in water suspensions. Cytotoxicity was also investigated and compared with that of the parent triterpenoids, showing enhanced effect of 18 that was the most successful derivative of the prepared series with sufficient balance between its cytotoxicity in CEM (IC50 = 11.7 ± 2.4 µM), HeLa (IC50 = 9.0 ± 0.7 µM) and G-361 (IC50 = 10.6 ± 5.5 µM) cancer cell lines, and toxicity in BJ (IC50 = 43.3 ± 1.5 µM). The calculated selectivity index values for 18 are SI = 3.9 (CEM), 4.8 (HeLa) and 4.4 (G-361). Additional compounds displaying cytotoxicity were 5, 7, 9 and 15, all of them showed comparable cytotoxicity with 18, in the investigated cancer cell lines; however, they were more toxic in BJ than 18.

Saponins of Selected Triterpenoids as Potential Therapeutic Agents: A Review.

Saponins represent important natural derivatives of plant triterpenoids that are secondary plant metabolites. Saponins, also named glycoconjugates, are available both as natural and synthetic products. This review is focused on saponins of the oleanane, ursane, and lupane types of triterpenoids that include several plant triterpenoids displaying various important pharmacological effects. Additional convenient structural modifications of naturally-occurring plant products often result in enhancing the pharmacological effects of the parent natural structures. This is an important objective for all semisynthetic modifications of the reviewed plant products, and it is included in this review paper as well. The period covered by this review (2019-2022) is relatively short, mainly due to the existence of previously published review papers in recent years.

Novel cytotoxic 1,10-phenanthroline-triterpenoid amphiphiles with supramolecular characteristics capable of coordinating 64Cu(II) labels.

1,10-Phenanthroline was decorated with triterpenoid-based substituents bearing additional spermine units to form amphiphilic molecules. The synthetic procedure designed for the new phenanthroline-triterpenoid amphiphiles is described in detail. Besides 1,10-phenanthroline, all target structures bear 1,4-disubstituted 1,2,3-triazole rings. The target compounds self-assembled into either helical-like or sheet-like nanostructures, depending on the structure of the target molecule, either based on betulinic acid or oleanolic acid, and on the way of binding spermine subunits to the rest of the molecules. They also proved their ability to coordinate 64Cu(II) ions. Finally, the target compounds showed cytotoxicity that was partly dependent on the formation of nanostructures.

Selected plant triterpenoids and their amide derivatives in cancer treatment: A review.

Medicinal plants have been used to treat different diseases throughout the human history namely in traditional medicine. Most of the plants mentioned in this review article belong among them, including those that are widely spread in the nature, counted frequently to be food and nutrition plants and producing pharmacologically important secondary metabolites. Triterpenoids represent an important group of plant secondary metabolites displaying emerging pharmacological importance. This review article sheds light on four selected triterpenoids, oleanolic, ursolic, betulinic and platanic acid, and on their amide derivatives as important natural or semisynthetic agents in cancer treatment, and, in part, in pathogenic microbe treatment. A literature search was made in the Web of Science for the given key words covering the required area of secondary plant metabolites and their amide derivatives. The most recently published findings on the biological activity of the selected triterpenoids, and on the structures and biological activity of their relevant amide derivatives have been summarized therein. Mainly anti-cancer effects, and, in part, antimicrobial and other effects of the four selected triterpenoids and their amide derivatives have also been reviewed. A comparison of the effects of the parent plant products and those of their amide derivatives has been made.

Acid-Responsive Nanoporphyrin Evolution for Near-Infrared Fluorescence-Guided Photo-Ablation of Biofilm.

Combating biofilm infections remains a challenge due to the shield and acidic conditions. Herein, an acid-responsive nanoporphyrin (PN3-NP) based on the self-assembly of a water-soluble porphyrin derivative (PN3) is constructed. Additional kinetic control sites formed by the conjugation of the spermine molecules to a porphyrin macrocycle make PN3 self-assemble into stable nanoparticles (PN3-NP) in the physiological environment. Noteworthily, near-infrared (NIR) fluorescence monitoring and synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) effects of PN3-NP can be triggered by the acidity in biofilms, accompanied by intelligent transformation into dot-like nanospheres. Thus, damage to normal tissue is effectively avoided and accurate diagnosis and treatment of biofilms is achieved successfully. The good results of fluorescence imaging-guided photo-ablation of antibiotic-resistant strains methicillin-resistant Staphylococcus aureus (MRSA) biofilms verify that PN3-NP is a promising alternative to antibiotics. Meanwhile, this strategy also opens new horizons to engineer smart nano-photosensitizer for accurate diagnosis and treatment of biofilms.

From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues.

This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.

Novel Oleanolic Acid-Tryptamine and -Fluorotryptamine Amides: From Adaptogens to Agents Targeting In Vitro Cell Apoptosis.

BACKGROUND: Oleanolic acid is a natural plant adaptogen, and tryptamine is a natural psychoactive drug. To compare their effects of with the effect of their derivatives, tryptamine and fluorotryptamine amides of oleanolic acid were designed and synthesized. METHODS: The target amides were investigated for their pharmacological effect, and basic supramolecular self-assembly characteristics. Four human cancer cell lines were involved in the screening tests performed by standard methods. RESULTS: The ability to display cytotoxicity and to cause selective cell apoptosis in human cervical carcinoma and in human malignant melanoma was seen with the three most active compounds of the prepared series of compounds. Tryptamine amide of (3ß)-3-(acetyloxy)olean-12-en-28-oic acid (3a) exhibited cytotoxicity in HeLa cancer cell lines (IC50 = 8.7 ± 0.4 µM) and in G-361 cancer cell lines (IC50 = 9.0 ± 0.4 µM). Fluorotryptamine amides of (3ß)-3-(acetyloxy)olean-12-en-28-oic acid (compounds 3b and 3c) showed cytotoxicity in the HeLa cancer cell line (IC50 = 6.7 ± 0.4 µM and 12.2 ± 4.7 µM, respectively). The fluorotryptamine amide of oleanolic acid (compound 4c) displayed cytotoxicity in the MCF7 cancer cell line (IC50 = 13.5 ± 3.3 µM). Based on the preliminary UV spectra measured in methanol/water mixtures, the compounds 3a-3c were also found to self-assemble into supramolecular systems. Conclusions: An effect of the fluorine atom present in the molecules on self-assembly was observed with 3b. Enhanced cytotoxicity has been achieved in 3a-4c in comparison with the effect of the parent oleanolic acid (1) and tryptamine. The compounds 3a-3c showed a strong induction of apoptosis in HeLa and G-361 cells after 24 h.

Triterpenoid-PEG Ribbons Targeting Selectivity in Pharmacological Effects.

(1) Background: To compare the effect of selected triterpenoids with their structurally resembling derivatives, designing of the molecular ribbons was targeted to develop compounds with selectivity in their pharmacological effects. (2) Methods: In the synthetic procedures, Huisgen 1,3-dipolar cycloaddition was applied as a key synthetic step for introducing a 1,2,3-triazole ring as a part of a junction unit in the molecular ribbons. (3) Results: The antimicrobial activity, antiviral activity, and cytotoxicity of the prepared compounds were studied. Most of the molecular ribbons showed antimicrobial activity, especially on Staphylococcus aureus, Pseudomonas aeruginosa, and Enterococcus faecalis, with a 50-90% inhibition effect (c = 25 µg·mL-1). No target compound was effective against HSV-1, but 8a displayed activity against HIV-1 (EC50 = 50.6 ± 7.8 µM). Cytotoxicity was tested on several cancer cell lines, and 6d showed cytotoxicity in the malignant melanoma cancer cell line (G-361; IC50 = 20.0 ± 0.6 µM). Physicochemical characteristics of the prepared compounds were investigated, namely a formation of supramolecular gels and a self-assembly potential in general, with positive results achieved with several target compounds. (4) Conclusions: Several compounds of a series of triterpenoid molecular ribbons showed better pharmacological profiles than the parent compounds and displayed certain selectivity in their effects.

Rapid Self-Healing and Thixotropic Organogelation of Amphiphilic Oleanolic Acid-Spermine Conjugates.

Natural and abundant plant triterpenoids are attractive starting materials for the synthesis of conformationally rigid and chiral building blocks for functional soft materials. Here, we report the rational design of three oleanolic acid-triazole-spermine conjugates, containing either one or two spermine units in the target molecules, using the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction. The resulting amphiphile-like molecules 2 and 3, bearing just one spermine unit in the respective molecules, self-assemble into highly entangled fibrous networks leading to gelation at a concentration as low as 0.5% in alcoholic solvents. Using step-strain rheological measurements, we show rapid self-recovery (up to 96% of the initial storage modulus) and sol ⇔ gel transition under several cycles. Interestingly, rheological flow curves reveal the thixotropic behavior of the gels. To the best of our knowledge, this kind of behavior was not shown in the literature before, neither for a triterpenoid nor for its derivatives. Conjugate 4, having a bolaamphiphile-like structure, was found to be a nongelator. Our results indicate that the position and number of spermine units alter the gelation properties, gel strength, and their self-assembly behavior. Preliminary cytotoxicity studies of the target compounds 2-4 in four human cancer cell lines suggest that the position and number of spermine units affect the biological activity. Our results also encourage exploring other triterpenoids and their derivatives as sustainable, renewable, and biologically active building blocks for multifunctional soft organic nanomaterials.

Diphenylurea-derived cytokinin oxidase/dehydrogenase inhibitors for biotechnology and agriculture.

Increasing crop productivity is our major challenge if we are to meet global needs for food, fodder and fuel. Controlling the content of the plant hormone cytokinin is a method of improving plant productivity. Cytokinin oxidase/dehydrogenase (CKO/CKX) is a major target in this regard because it degrades cytokinins. Here, we describe the synthesis and biological activities of new CKX inhibitors derived mainly from diphenylurea. They were tested on four CKX isoforms from maize and Arabidopsis, where the best compounds showed IC50 values in the 10-8 M concentration range. The binding mode of the most efficient inhibitors was characterized from high-resolution crystal complexed structures. Although these compounds do not possess intrinsic cytokinin activity, we have demonstrated their tremendous potential for use in the plant tissue culture industry as well as in agriculture. We have identified a key substance, compound 19, which not only increases stress resistance and seed yield in Arabidopsis, but also improves the yield of wheat, barley and rapeseed grains under field conditions. Our findings reveal that modulation of cytokinin levels via CKX inhibition can positively affect plant growth, development and yield, and prove that CKX inhibitors can be an attractive target in plant biotechnology and agriculture.

Synthesis and Pharmacological Effects of Diosgenin-Betulinic Acid Conjugates.

The target diosgenin-betulinic acid conjugates are reported to investigate their ability to enhance and modify the pharmacological effects of their components. The detailed synthetic procedure that includes copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction), and palladium-catalyzed debenzylation by hydrogenolysis is described together with the results of cytotoxicity screening tests. Palladium-catalyzed debenzylation reaction of benzyl ester intermediates was the key step in this synthetic procedure due to the simultaneous presence of a 1,4-disubstituted 1,2,3-triazole ring in the molecule that was a competing coordination site for the palladium catalyst. High pressure (130 kPa) palladium-catalyzed procedure represented a successful synthetic step yielding the required products. The conjugate 7 showed selective cytotoxicity in human T-lymphoblastic leukemia (CEM) cancer cells (IC50 = 6.5 ± 1.1 µM), in contrast to the conjugate 8 showing no cytotoxicity, and diosgenin (1), an adaptogen, for which a potential to be active on central nervous system was calculated in silico. In addition, 5 showed medium multifarious cytotoxicity in human T-lymphoblastic leukemia (CEM), human cervical cancer (HeLa), and human colon cancer (HCT 116). Betulinic acid (2) and the intermediates 3 and 4 showed no cytotoxicity in the tested cancer cell lines. The experimental data obtained are supplemented by and compared with the in silico calculated physico-chemical and absorption, distribution, metabolism, and excretion (ADME) parameters of these compounds.

Decorative Magnolia Plants: A Comparison of the Content of Their Biologically Active Components Showing Antimicrobial Effects.

Magnolia plants are used both as food supplements and as cosmetic and medicinal products. The objectives of this work consisted of preparing extracts from leaves and flowers of eight Magnolia plants, and of determining concentrations of magnolol (1 to 100 mg·g-1), honokiol (0.11 to 250 mg·g-1), and obovatol (0.09 to 650 mg·g-1), typical neolignans for the genus Magnolia, in extracts made by using a methanol/water (80/20) mixture. The tested Magnolia plants, over sixty years old, were obtained from Pruhonický Park (Prague area, Czech Republic): M. tripetala MTR 1531, M. obovata MOB 1511, and six hybrid plants Magnolia × pruhoniciana, results of a crossbreeding of M. tripetala MTR 1531 with M. obovata MOB 1511. The identification of neolignans was performed by HRMS after a reversed-phase high-performance liquid chromatography (RP-HPLC) fractionation of an extract from M. tripetala MTR 1531. The highest concentrations of neolignans were found in the flowers, most often in their reproductive parts, and obovatol was the most abundant in every tested plant. The highest concentrations of neolignans were detected in parent plants, and lower concentrations in hybrid magnolias. Flower extracts from the parent plants M. tripetala MTR 1531 and M. obovata MOB 1511, flower extracts from the hybrid plants Magnolia × pruhoniciana MPR 0271, MPR 0151, and MPR 1531, and leaf extract from the hybrid plant Magnolia × pruhoniciana MPR 0271 inhibited growth of Staphylococcus aureus.

Spermine amides of selected triterpenoid acids: dynamic supramolecular system formation influences the cytotoxicity of the drugs.

Cancer is a global disease of great importance, and the need for novel cytotoxic drugs is still eminent. A series of spermine amides of several selected triterpene acids (betulonic, heterobetulonic, oleanolic, ursolic and platanic acid) have been synthesized to search for new cytotoxic and antimicrobial agents. The compounds have also been subjected to the investigation of their physico-chemical characteristics (ability to self-assemble), and to an in silico comparative calculation of their physico-chemical and ADME parameters. In the in vitro screening tests with several target compounds (8a-8c and 11c), their cytotoxicity changed with prolonged time, which appeared to be a result of formation of dynamic supramolecular networks. This phenomenon is important in investigation of the effect of self-assembly on biological activity. The most important compounds in this series were spermine derivatives of heterobetulonic acid (3b) and ursolic acid (8b), showing cytotoxicity <5 µM and <10 µM, respectively, on all tested cancer cell lines. Comparable cytotoxicity was also displayed by 13b, formerly a model compound prepared for testing of the synthetic procedures, the 1,2-diaminoethane derivative. The target compounds 3b and 8b displayed antimicrobial activity on Staphylococcus aureus, Streptococcus mutans and Listeria monocytogenes at a concentration 6.25 µM. Supramolecular characteristics of several compounds were documented by the TEM and SEM micrographs showing fibrous, partially helical, networks, and UV measurements showing changes in the intensity of UV signals, also indicating formation of supramolecular systems.

Recent Achievements in Medicinal and Supramolecular Chemistry of Betulinic Acid and Its Derivatives ‡.

The subject of this review article refers to the recent achievements in the investigation of pharmacological activity and supramolecular characteristics of betulinic acid and its diverse derivatives, with special focus on their cytotoxic effect, antitumor activity, and antiviral effect, and mostly covers a period 2015-2018. Literature sources published earlier are referred to in required coherences or from historical points of view. Relationships between pharmacological activity and supramolecular characteristics are included if such investigation has been done in the original literature sources. A wide practical applicability of betulinic acid and its derivatives demonstrated in the literature sources is also included in this review article. Several literature sources also focused on in silico calculation of physicochemical and ADME parameters of the developed compounds, and on a comparison between the experimental and calculated data.

Enhancing effect of cystamine in its amides with betulinic acid as antimicrobial and antitumor agent in vitro.

Amides of betulinic acid with cystamine were synthesized to investigate their antimicrobial and antitumor activity, and their influence on the cell cycle and cell apoptosis. The former target amide (6) displayed cytotoxicity in CEM cell line after 72 h of treatment (IC50 = 3.0 ±â€¯0.7 µM; TI = 20), and induced apoptosis by caspase-3/7 activation in CEM cells. The latter target amide (9) displayed antimicrobial activity against Streptococcus mutans (MIC 3.125 µM; MBC 3.125 µM) and Bacillus cereus (MIC 25 µM; MBC 25 µM). The achieved results demonstrate enhancing of their biological activity over that of the parent compounds. However, two intermediate compounds (2 and 7) displayed either considerable cytotoxicity (2; 7.5 ±â€¯0.8 µM; TI = 10, against G361) or antimicrobial activity (7; both against Actinomyces odontolycus and Clostridium perfrigens with MIC 12.5 µM and MBC 12.5 µM). The experimental data were compared with the in silico calculated physico-chemical and ADME parameters of the target compounds, including successful intermediates.

Picolyl amides of betulinic acid as antitumor agents causing tumor cell apoptosis.

A series of picolyl amides of betulinic acid (3a-3c and 6a-6c) was prepared and subjected to the cytotoxicity screening tests. Structure-activity relationships studies resulted in finding differences in biological activity in dependence on o-, m- and p-substitution of the pyridine ring in the target amides, when cytotoxicity data of 3a-3c and 6a-6c were obtained and compared. The amides 3b and 3a displayed cytotoxicity (given in the IC50 values) in G-361 (0.5 ±â€¯0.1 µM and 2.4 ±â€¯0.0 µM, respectively), MCF7 (1.4 ±â€¯0.1 µM and 2.2 ±â€¯0.2 µM, respectively), HeLa (2.4 ±â€¯0.4 µM and 2.3 ±â€¯0.5 µM, respectively) and CEM (6.5 ±â€¯1.5 µM and 6.9 ±â€¯0.4 µM, respectively) tumor cell lines, and showed weak effect in the normal human fibroblasts (BJ). Selectivity against all tested cancer cells was determined and compared to normal cells with therapeutic index (TI) between 7 and 100 for compounds 3a and 3b. The therapeutic index (TI = 100) was calculated for human malignant melanoma cell line (G-361) versus normal human fibroblasts (BJ). The cytotoxicity of other target amides (3c and 6a-6c) revealed lower effects than 3a and 3b in the tested cancer cell lines.

Amphiphilic derivatives of (3ß,17ß)-3-hydroxyandrost-5-ene-17-carboxylic acid.

A series of amphiphilic derivatives of (3ß,17ß)-3-hydroxyandrost-5-ene-17-carboxylic acid (1) with the polyamine spermine and three other diamines, 1,2-diaminoethane, piperazine and cadaverine, were synthesized and their antimicrobial activity and cytotoxicity were investigated. Among the target compounds, several ones showed antimicrobial activity on Gram positive and Gram negative microorganisms. The most active compounds were 20 (Streptococcus mutans CCM 7409, 3.125 µM), 16 (Streptococcus mutans CCM 7409, 12.5 µM) and 10d (Escherichia coli CCM 3954, 12.5 µM). In addition, compounds 5d, 10d, 13 and 20 displayed cytotoxicity on CEM (12.1 ±â€¯2.1 µM, 7.6 ±â€¯1.0 µM, 19.0 ±â€¯0.4 µM and 5.9 ±â€¯0.7 µM, respectively). Two additional compounds displayed medium cytotoxicity on CEM, 5a (34.6 ±â€¯5.2 µM) and 5c (37.7 ±â€¯5.9 µM). The compound 13 and 20 displayed high toxicity also on normal fibroblasts.

BODIPY-based fluorescent liposomes with sesquiterpene lactone trilobolide.

Like thapsigargin, which is undergoing clinical trials, trilobolide is a natural product with promising anticancer and anti-inflammatory properties. Similar to thapsigargin, it has limited aqueous solubility that strongly reduces its potential medicinal applications. The targeted delivery of hydrophobic drugs can be achieved using liposome-based carriers. Therefore, we designed a traceable liposomal drug delivery system for trilobolide. The fluorescent green-emitting dye BODIPY, cholesterol and trilobolide were used to create construct 6. The liposomes were composed of dipalmitoyl-3-trimethylammoniumpropane and phosphatidylethanolamine. The whole system was characterized by atomic force microscopy, the average size of the liposomes was 150 nm in width and 30 nm in height. We evaluated the biological activity of construct 6 and its liposomal formulation, both of which showed immunomodulatory properties in primary rat macrophages. The uptake and intracellular distribution of construct 6 and its liposomal formulation was monitored by means of live-cell fluorescence microscopy in two cancer cell lines. The encapsulation of construct 6 into the liposomes improved the drug distribution in cancer cells and was followed by cell death. This new liposomal trilobolide derivative not only retains the biological properties of pure trilobolide, but also enhances the bioavailability, and thus has potential for the use in theranostic applications.