Category: Phytochemicals

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  buy gabapentin without prescription 7 showed selective cytotoxicity in human T-lymphoblastic leukemia (CEM) cancer cells (IC50 = 6.5 ± 1.1 µM), in contrast to the conjugate  backstage 8 showing no cytotoxicity, and diosgenin ( Atibaia 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.

Diosgenin, (3β,25R)-spirost-5-en-3-ol, is a steroid sapogenin part of the saponin dioscin found in the tubers of Dioscorea zingiberensis C. H. Wright or Trigonella foenum-graecum L. and in numbers of legumes. Diosgenin is a widely used precursor in the synthesis of sexual hormones, peroral contraceptives and other steroids in the pharmaceutical industry. It is an adaptogen, displaying non-steroidogenic activity along with other beneficial effects. Diosgenin is unable to bind metal ions, and therefore, the change made from more traditional cholesterol/cholesterylamine system to diosgenin could influence the overall conformation of the bivalent structures, modifying the metal ions chelating properties. Saponins are always species formed from an aglycone and several monosaccharide units, the presence of which increases the solubility of saponins in natural aqueous media. Diosgenin is not metabolized in the human body, and it is considered to represent a safe natural drug. It has also been investigated for treating hyperglycemia, hypercholesterolemia, hypertriacylglycerolemia, and Alzheimer’s disease.
Betulinic acid, 3β-hydroxylup-20(29)-en-28-oic acid, is a pharmacologically perspective triterpenoid plant product with a broad spectrum of effects, e.g., antitumor, anti-HIV, cytostatic, and anti-inflammatory. It can be obtained from the bark of Betula pendula Roth, widely distributed in Europe, and from a number of subtropical and tropical plants. (Molecules. 2020 Aug; 25(15): 3546.)

Mitocanic Di- and Triterpenoid Rhodamine B Conjugates

The combination of the “correct” triterpenoid, the “correct” spacer and rhodamine B (RhoB) seems to be decisive for the ability of the conjugate to accumulate in mitochondria. So far, several triterpenoid rhodamine B conjugates have been prepared and screened for their cytotoxic activity. To obtain cytotoxic compounds with EC50 values in a low nano-molar range combined with good tumor/non-tumor selectivity, the Rho B unit has to be attached via an amine spacer to the terpenoid skeleton. To avoid spirolactamization, secondary amines have to be used. First results indicate that a homopiperazinyl spacer is superior to a piperazinyl spacer. Hybrids derived from maslinic acid or tormentic acid are superior to those from oleanolic, ursolic, glycyrrhetinic or euscaphic acid. Thus, a tormentic acid-derived RhoB conjugate 32, holding a homopiperazinyl spacer can be regarded, at present, as the most promising candidate for further biological studies.

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Mitochondrial membranes of malignant cells hold an increased membrane potential compared to non–malignant cells. This effect fosters the accumulation of cationic molecules, hence inducing high selectivity for mitocans holding a (more or less) lipophilic cation such as a rhodamine scaffold. The same effect applies for triphenylphosphonium cations and to a small extent for quaternary ammonium ions, zwitterionic N-oxides and triterpenes substituted with BODIPYs or a safirinium moiety [67].
To date, hybrid molecules have been prepared from oleanolic acid (OA, Figure 2), ursolic acid (UA), glycyrrhetinic acid (GA), betulinic acid (BA), maslinic acid (MA), augustic acid (AU), 11-keto-β-boswellic acid (KBA), asiatic acid (AA), tormentic acid (TA) and euscaphic acid (EA).
OA-derived RhoB conjugates appear to be superior to analog UA-derived compounds in the majority of cases with respect to their cytotoxicity. Although AKBA-derived derivatives have good cytotoxicity properties, they were found to be less cytotoxic compared to other triterpene carboxylic acid derivatives, but they often showed better tumor cell/non-tumor cell selectivity. So far, the best cytotoxicity properties have been found for MA-, EA- and TA-derived derivatives. These allowed the transition to compounds of nano-molar activity, while many other triterpene carboxylic acid derivatives were cytotoxic only on a micro-molar concentration range. MA- derived derivatives seem to be approximately equivalent to EA-derived compounds. They are currently only surpassed in many tumor cell lines only by the analogous derivatives from TA. From results available so far, it can be concluded that compounds holding a homopiperazinyl spacer are superior to those with a piperazinyl spacer. This underlines the importance of the spacer for obtaining good cytotoxicity properties. (Molecules. 2020 Nov; 25(22): 5443.)

Bioactive Compounds for Skin Health

Human skin is continually changing. The condition of the skin largely depends on the individual’s overall state of health. A balanced diet plays an important role in the proper functioning of the human body, including the skin. The present study draws attention to bioactive substances, i.e., vitamins, minerals, fatty acids, polyphenols, and carotenoids, with a particular focus on their effects on the condition of the skin. The aim of the study was to review the literature on the effects of bioactive substances on skin parameters such as elasticity, firmness, wrinkles, senile dryness, hydration and color, and to define their role in the process of skin ageing.

The skin is the largest organ of the human body. It is composed of the epidermis, which consists of epithelial tissue, and the dermis, which consists of connective tissue. Under the dermis, there is a layer of subcutaneous tissue called the hypodermis (Figure 1). The epidermis comprises a horny layer (stratum corneum), a clear layer (stratum lucidum), a granular layer (stratum granulosum), a spinous layer (stratum spinosum) and a basal layer (stratum basale). Apart from keratinocytes—cells involved in keratinization—the five-layer epidermis also contains pigment cells and melanocytes, as well as Langerhans cells, mastocytes, and Merkel cells. It is closely connected to the dermis underneath by the basement membrane. The dermis, which comprises a papillary layer (primarily loose connective tissue) and a reticular layer (dense connective tissue), contains fibroblasts responsible for the production of collagen, elastin, and glycosaminoglycans (GAGs), as well as numerous blood vessels, nerve endings, and appendages, such as hair follicles and sweat and sebaceous glands. The subcutaneous tissue consists of loose connective tissue containing fat cells (adipocytes) forming fat lobules.

Features characteristic of mature skin include wrinkles, a loss of elasticity, changes in color, uneven pigmentation and discoloring, dryness, foci of abnormal epidermal keratosis, telangiectasias, susceptibility to irritation, and slower skin regeneration and healing. One of the most common dermatological and cosmetic concerns is skin ageing: a natural, complex process influenced by two mechanisms—intrinsic (genetic, chronological) ageing resulting from the passage of time, and extrinsic ageing (photoaging), caused by environmental factors (including UV radiation, environmental pollution and cigarette smoke). The two processes overlap and are closely linked to increased reactive oxygen species (ROS) and oxidative stress in the skin. Both the intrinsic and extrinsic processes are associated with biochemical disturbances (e.g., the excessive formation of oxygen radicals, leading to protein and DNA damage, amino acid racemization, and non-enzymatic glycosylation, leading to the abnormal cross-linking of collagen fibers and other structural proteins), as well as changes in the physical, morphological and physiological properties of the epidermis and dermis. These include disturbances in the function of the epidermal barrier, the flattening of the dermal–epidermal junction, a reduced number and activity of fibroblasts, the accumulation of abnormal elastin fibers (elastosis), and the impaired functioning of Langerhans cells. (Nutrients. 2021 Jan; 13(1): 203.)

Potential protective effect of Trans-10-hydroxy-2-decenoic acid on the inflammation induced by Lipoteichoic acid

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Royal jelly (RJ) is known as a functional food for its diverse health-beneficial properties and complicated chemical compositions. Trans-10-hydroxy-2-decenoic acid (10-HDA) is the exclusive lipid component in RJ. In the present study, the in vitro anti-inflammatory effect of 10-HDA in LTA (Lipoteichoic acid from Staphylococcus aureus) induced RAW 264.7 macrophages are evaluated. The results showed that 10-HDA had potent, dose-dependent inhibitory effects on the release of major inflammatory mediators and NO. Several key inflammatory genes, including IL-1β, IL-6, MCP-1 and COX-2 have also been suppressed by 10-HDA. Furthermore, the effects of 10-HDA on LTA-induced pulmonary damage were also examined in mice. It was found that the administration of 10-HDA (100 mg/kg) can provide protective effects by attenuating lung histopathological changes and modulating the secretion of LTA-stimulated inflammatory cytokines in mice, such as IL-10, MCP-1 and TNF-α. Conclusively, the results reveal the potent anti-inflammatory properties of 10-HDA and provide biological information for the future application.(Journal of Functional Foods. Volume 45, June 2018, Pages 491-498.)

Perspectives on Biologically Active Camptothecin Derivatives

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Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects.


Camptothecin (CPT) is a pentacyclic alkaloid isolated by Wall et al. in the early 1960s from the Chinese tree Camptotheca acuminata. This compound attracted immediate interest as a potential cancer chemotherapeutic agent due to its impressive activity against leukemias and various solid tumors in experimental systems. Due to CPT’s negligible water solubility, clinical trials were initiated using the water-soluble sodium salt of CPT in the early 1970s. The trials were suspended in the 1970s due to lower efficacy of 2, accompanied by unpredictable and severe levels of toxicity, including hemorrhagic cystitis and myelotoxicity. Interest in CPT then subsided for over a decade. Revived attention resulted from the breakthrough discovery of DNA topoisomerase I (Topo I) as a therapeutic target for CPT. This discovery put CPT back on the frontlines of anticancer drug development in the late 1980s. Accordingly, CPT’s total synthesis, mechanism of action, structure–activity relationship (SAR), analog synthesis as well as pharmacology, formulation, drug delivery, preclinical studies and clinical trials have been studied extensively. Recent interesting research approaches include using prodrug concepts and drug delivery systems for CPT.
As the result of these renewed research efforts, three CPT analogues, topotecan (TPT), irinotecan (CPT-11), and belotecan (CKD-602), received governmental approval for the clinical treatment of ovarian, small-cell lung, and refractory colorectal cancers. Three additional water-soluble analogues, exatecan (DX-8951f) lurtotecan (GG-211), and sinotecan, are currently under clinical evaluation. (Med Res Rev. 2015 Jul; 35(4): 753–789.)

Natural product-derived phytochemicals as potential agents against coronaviruses: A review

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Coronaviruses are responsible for a growing economic, social and mortality burden, as the causative agent of diseases such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), avian infectious bronchitis virus (IBV) and COVID-19. However, there is a lack of effective antiviral agents for many coronavirus strains. Naturally existing compounds provide a wealth of chemical diversity, including antiviral activity, and thus may have utility as therapeutic agents against coronaviral infections. The PubMed database was searched for papers including the keywords coronavirus, SARS or MERS, as well as traditional medicine, herbal, remedy or plants, with 55 primary research articles identified. The overwhelming majority of publications focussed on polar compounds. Compounds that show promise for the inhibition of coronavirus in humans include scutellarein, silvestrol, tryptanthrin, saikosaponin B2, quercetin, myricetin, caffeic acid, psoralidin, isobavachalcone, and lectins such as griffithsin. Other compounds such as lycorine may be suitable if a therapeutic level of antiviral activity can be achieved without exceeding toxic plasma concentrations. It was noted that the most promising small molecules identified as coronavirus inhibitors contained a conjugated fused ring structure with the majority being classified as being polyphenols.

Coronaviruses (CoVs) belong to the family Coronaviridae, subfamily Coronavirinae and are large (genome size 26−32 kb; Wu et al., 2020a), enveloped, positive-sense single-stranded ribonucleic acid (RNA) viruses that can infect both animals and humans. Based on their genotypic and serological characteristics, the viruses are subdivided into four genera: Alpha-, Beta-, Gamma-, and Deltacoronavirus (Chu et al., 2020; Lu et al., 2015). At present, all identified CoVs that are capable of infecting humans belong to the first two genera. These include the alphacoronaviruses (αCoVs) HCoV-NL63 (Human CoV-NL63) and HCoV-229E and the betacoronaviruses (βCoVs) HCoV-OC43 (Human CoV-OC43), HKU1 (Human CoV), SARS-CoV (Severe Acute Respiratory Syndrome CoV), and MERS-CoV (Middle Eastern Respiratory Syndrome CoV) (Lu et al., 2015). In the past two decades there have been three epidemics caused by the betaCoVs, namely SARS in 2002−03, MERS in 2012 and COVID-19, first identified in 2019. (Virus Res. 2020 Jul 15;284:197989. )