Pregnane Glycosides Research Articles

Cynanotophyllosides E-F, two minor pregnane glycosides from the roots of cultivated Cynanchum otophyllum

Cynanotophyllosides E-F, two new minor pregnane glycosides were isolated from the antidepressant active fraction of cultivated Cynanchum otophyllum, and their structures were determined as 12-O-vanilloyl-deacetylmetaplexigenin 3-O--D-glucopyranosyl-(1→4)--D-glucopyranosyl-(1→4)--D-cymaropyranosyl-(1→4)--D-oleandropyranosyl-(1→4)--D-digitoxopyranoside, and 12-O-nicotinoyl-deacetylmetaplexigenin 3-O--D-glucopyranosyl-(1→4)--D-glucopyranosyl-(1→4)--D-cymaropyranosyl-(1→4)--D-oleandropyranosyl-(1→4)--D-cymaropyranoside respectively, with the combination of spectroscopic and chemical analysis.

Quadrangulosides A–F: new pregnane glycosides from Caralluma quadrangula

The phytochemical investigation of Caralluma quadrangula aerial parts yielded six new pregnane glycosides, quadrangulosides A-F (1-6), in addition to nine known pregnane glycosides and three known flavone glycosides. Structures of isolated phyto-constituents were elucidated via spectroscopic 1D-, 2D-NMR and spectrometric ESI-MS spectra.

Plant in vitro cultures: A promising and emerging technology for the feasible production of antidiabetic metabolites in Caralluma tuberculata.

Caralluma tuberculata, a medicinal and edible plant of the genus Caralluma, belongs to the family Asclepiadaceae. Traditionally, its succulent stems are used as folk medicine for life-threatening diabetes mellitus (DM) disease. Its antidiabetic potential is ascribed to the presence of various secondary metabolites (e.g., pregnane glycosides, flavone glycosides, megastigmane glycosides, polyphenols, ferulic acid, quercetin, and bitter principles, among others) that act as effective and safe antidiabetic agents. The mechanisms of these bioactive secondary metabolites in C. tuberculata herbal medicine include lowering the blood glucose level, stimulating B cells of the pancreas to release more insulin, enhancing the sensitivity of the insulin receptor, inhibiting the action of glucagon and the hydrolysis of glycogen, and increasing the use of glucose in tissues and organ. However, overexploitation, alterations in natural environmental conditions, lower seed viability, and slow growth rate are responsible for the extinction of species from natural habitats, then becoming critically endangered species according to the International Union for Conservation of Nature Red List categories. Therefore, its limited availability does not meet the higher worldwide market demand of C. tuberculata as an antidiabetic drug. Thus, for its conservation and sustainable utilization, researchers across the globe are working on devising strategies to conserve and improve biomass along with the secondary metabolite profiles of C. tuberculata using in vitro approaches. The current review describes the recent progress on antidiabetic phytoconstituents, their cellular mechanisms, and their subsequent clinical outcomes in the drug discovery management of DM. Moreover, in vitro methods such as callus culture, micropropagation, and nano-elicitation strategies for conserving and producing bioactive secondary metabolites have been concisely reviewed and discussed.

Effects of ecological factors on phytochemical and nutritional composition of Caralluma tuberculata N. E. Brown

The effects of global warming on vegetation phenology are widespread. A study in Southern Khyber Pakhtunkhwa, Pakistan investigated the effects of ecological factors including precipitation and temperature on phytochemical, and nutritional composition of wild Caralluma tuberculata N. E. Brown. Photosynthetic pigments, saponins, crude proteins, crude fats, moisture, and ash were significantly higher (p < 0.05) in the plants of Shaker Darra area than in the plants of Lakki Marwat, Darra Adam Khel, and Spin Wam areas. Pearson correlation explains a high correlation existing between the annual rainfall and temperature with that of pregnane glycosides. The current study concluded that mainly rainfall influences the phytochemical, nutritional, and physiological profiles of C. tuberculata.

Russelioside A, a Pregnane Glycoside from Caralluma tuberculate, Inhibits Cell-Intrinsic NF-κB Activity and Metastatic Ability of Breast Cancer Cells.

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a potential target for inflammatory-breast cancer treatment as it participates in its pathogenesis, such as tumor initiation, progression, survival, metastasis, and recurrence. In this study, we aimed to discover a novel anti-cancer treatment from natural products by targeting NF-κB activity. Using the 4T1-NFκB-luciferase reporter cell line, we tested three pregnane glycosides extracted from the herb Caralluma tuberculata and discovered that Russelioside A markedly suppressed NF-κB activity in breast cancer. Russelioside A inhibited NF-κB (p65) transcriptional activity and its phosphorylation. Following NF-κB inhibition, Russelioside A exerted anti-proliferative and anti-metastatic effects in breast cancer cells in vitro. Moreover, it inhibited the NF-κB constitutive expression of downstream pathways, such as VEGF-b, MMP-9, and IL-6 in 4T1 cells. In addition, it reduced the metastatic capacity in a 4T1 breast cancer model in vivo. Collectively, our conclusions reveal that Russelioside A is an attractive natural compound for treating triple-negative breast cancer growth and metastasis through regulating NF-κB activation.

New Pregnane Glycosides from Mandevilla dardanoi and Their Anti-Inflammatory Activity.

Mandevilla Lindl. is an important genus of the Apocynaceae family, not only as ornamental plants but also for its medicinal uses. In Brazil, Mandevilla species are indicated to treat asthma and skin infections, their anti-inflammatory potential and wound healing properties are also reported in the literature. Concerning their chemical composition, this group of plants is a conspicuous producer of pregnane glycosides. Mandevilla dardanoi is an endemic species from the Brazilian semiarid region not studied by any phytochemical methods. In view of the medicinal potential of Mandevilla species, this study aimed to isolate new pregnane glycosides from M. dardanoi. To achieve this main goal, modern chromatography techniques were employed. Five new pregnane glycosides, dardanols A-E, were isolated from the roots of M. dardanoi by HPLC. Their structures were determined using extensive 1D and 2D-NMR and mass spectrometry (MSn and HRESIMS) data. The cytotoxicity and the anti-inflammatory potential of these compounds were evaluated. The first was evaluated by measuring proinflammatory cytokines and nitric oxide production by stimulated macrophages. Dardanols were able to inhibit the production of nitric oxide and reduce IL-1β and TNF-α. The current work demonstrates the chemodiversity of Brazilian semiarid species and contributes to amplifying knowledge about the biological potential of the Mandevilla genus.

Inhibition mechanism of alpha-amylase, a diabetes target, by a steroidal pregnane and pregnane glycosides derived from Gongronema latifolium Benth.

Alpha-amylase is widely exploited as a drug target for preventing postprandial hyperglycemia in diabetes and other metabolic diseases. Inhibition of this enzyme by plant-derived pregnanes is not fully understood. Herein, we used in vitro, in silico, and in vivo studies to provide further insights into the alpha-amylase inhibitory potential of selected pregnane-rich chromatographic fractions and four steroidal pregnane phytochemicals (SPPs), viz: marsectohexol (P1), 3-O-[6-deoxy-3-O-methyl-β-D-allopyranosyl-(1→14)-β-D-oleandropyranosyl]-11,12-di-O-tigloyl-17β-marsdenin (P2), 3-O-[6-deoxy-3-O-methyl-β-D-allopyranosyl-(1→4)-β-D-oleandropyranosyl]-17β-marsdenin (P3), and 3-O-[6-deoxy-3-O-methyl-β-D-allopyranosyl-(1→4)-β-D-canaropyranosyl]-17β-marsdenin (P4) derived from Gongronema latifolium Benth. The results revealed that the SPPs source pregnane-rich chromatographic fractions and the SPPs (P1–P4) exhibited inhibitory potential against porcine pancreatic alpha-amylase in vitro. Compounds P1 and P2 with IC50 values 10.01 and 12.10 µM, respectively, showed greater inhibitory potential than the reference acarbose (IC50 = 13.47 µM). Molecular docking analysis suggests that the SPPs had a strong binding affinity to porcine pancreatic alpha-amylase (PPA), human pancreatic alpha-amylase (HPA), and human salivary alpha-amylase (HSA), interacting with the key active site residues through an array of hydrophobic interactions and hydrogen bonds. The strong interactions of the SPPs with Glu233 and Asp300 residues may disrupt their roles in the acid-base catalytic mechanism and proper orientation of the polymeric substrates, respectively. The interactions with human pancreatic amylase were maintained in a dynamic environment as indicated by the root mean square deviation, radius of gyration, surface accessible surface area, and number of hydrogen bonds computed from the trajectories obtained from a 100-ns molecular dynamics simulation. Key loop regions of HPA that contribute to substrate binding exhibited flexibility and interaction potential toward the compounds as indicated by the root mean square fluctuation. Furthermore, P1 significantly reduced blood glucose levels and area under the curve in albino rats which were orally challenged with starch. Therefore, Gongronema latifolium and its constituent SPPs may be exploited as inhibitors of pancreatic alpha-amylase as an oral policy for impeding postprandial blood glucose rise.

C21 Steroidal Glycosides from the Roots of Oxypetalum caeruleum.

The MeOH extract from dried roots of Oxypetalum caeruleum (Apocynaceae) plants yielded seventeen new pregnane glycosides, some of which had the acylated-ramanone or -isoramanone type aglycone. The structures of these compounds were established using NMR, MS spectroscopic analysis and chemical evidence.

Cortex periplocae modulates the gut microbiota to restrict colitis and colitis-associated colorectal cancer via suppression of pathogenic Th17 cells

Aberrant microbe-immune cell interaction is a predisposing factor in inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Cortex Periplocae is a famous traditional Chinese medicine with putative anti-rheumatoid arthritis and anti-dyspepsia effects. Here, we show that the Periploca sepium periplosides (PePs), a cardiac glycosides-free pregnane glycosides extract from root bark of Cortex Periplocae, alleviates colon inflammation, improves intestinal epithelial barrier function, and prevents colitis-associated tumorigenesis in mice with colitis and CAC. Mechanistically, PePs treatment modulates abnormal gut microbiota composition in model mice, especially enriches an anti-inflammatory commensal bacterium A. muciniphila BAA-835. We further demonstrate that the altered gut microbiota following PePs treatment plays an important role in modulation of intestinal Type 17 immunity in both colitis and CAC mouse model. Our results indicate that PePs may be used as a potential gut microbiota modulator to treat IBD and CAC.

Caralluma edulis (Apocynaceae): A Comprehensive Review on its Traditional Uses, Phytochemical Profile and Pharmacological Effects.

Caralluma edulis is a well-known species of the genus Caralluma from Apocynaceae, commonly known as chunga. Caralluma species are mostly succulent perennial herbs, several of which are edible species. The plant has an outstanding therapeutic background in the traditional system of treatment. It has been recommended for the treatment of a number medical disorders such as hypertension, Alzheimer's disease, rheumatism, gastric problems and leprosy. Traditionally the stem was boiled in water and this extract was then used to cure diabetes. The pharmacological effects of C. edulis have also been explored in various in vitro and in vivo experiments. In this regard, the extract of the plant exhibited strong antioxidant, and analgesic activity against inflammation as well as xylene-mediated ear edema as topical effects. The significant anti-hyperlipidemic effect of the plant extract is also reported. However, the extract was found insignificant in the reversal of alloxan-induced diabetes in the rabbit model at test doses. These pharmacological effects are strongly supported by the presence of different bioactive phytochemicals in the plant. These groups of compounds include sterols, terpenoids, flavonoids, and pregnane glycosides. C. edulis is a very potential member of the genus Caralluma with strong traditional history, phytochemistry and phytopharmacology, and needs further exploration for clinically used lead compounds. In this review, we have focused on combining different reported data on the traditional uses of the plant, its phytochemical profile and pharmacological effects in different experimental assay along with subsequent future prospects.

Arabincosides A-D, pregnane glycosides isolated from Caralluma arabica

The aqueous remained fraction after partitioning the crude ethanol extract with ether and methylene chloride of the aerial parts of Caralluma arabica yielded six pregnane glycosides, four of them were found to be new pregnane glycosides and were identified using spectral analysis (MS, 1D and 2DNMR) as 3β,14β, dihydroxypregn-5-en-20-one-3-O-β-d-glucopyranosyl-(1 → 4)-O-β-d-digitalopyranoside (arabincoside A), 3β,14β-dihydroxypregn-5-en-20-one-3-O-β-d-glucopyranosyl-(1 → 6)-O-β-d-glucopyranosyl-(1 → 4)-O-β-d-digitalopyranoside (arabincoside B), 12-β-O-benzoyl-3β, 12β, 14β, 20-tetrahydroxy-(20R)-pregn-5-ene-3-O-β-d-glucopyranosyl-(1 → 4)-β-d-cymaropyranosyl-(1 → 4)-β-d-cymaropyranoside (arabincoside C) and 12-β-O-benzoyl-3β, 12β, 14β, 20-tetrahydroxy-(20R)-pregn-5-ene-3-O-β-d-glucopyranosyl-(1 → 4)-β-d-glucopyranosyl-(1 → 4)-β-d-cymaropyranosyl-(1 → 4)-β-d-cymaropyranoside (arabincoside D). In addition, two known pregnane glycosides were also isolated and identified as russelioside D and russelioside C, previously isolated from C. russelliana.

Comprehensive polyoxypregnane glycosides report in Caralluma quadrangula using UPLC–ESI–Q–TOF and their antioxidant effects in human plasma

Caralluma quadrangula (Forssk.) N.E.Br. (Syns: = Stapelia quadrangula Forssk. = Monolluma quadrangula Forssk.) is an indigenous member of the genus Caralluma and it is a rather common species on rocky hillsides in the southwestern part of Saudi Arabia. Several members of this genus have found medicinal uses in the treatment of rheumatism, diabetes, leprosy and as antiseptics and disinfectants. All parts are edible but rather more bitter and can cause diarrhea.The present report was tentatively elucidated the structure of acylated and non-acylated polyoxypregnane glycosides from Caralluma quadrangula.The analyses were performed using an electrospray-ionization quadrupole time-of-flight (ESI-Q-TOF) mass spectrometer in both positive and negative ionization modes to explore fragmentation pathways. The antioxidant and prooxidant properties of the different mobility portions of human plasma were evaluated in vitro using thiobarbituric acid reactive substance assay (TBARS).The analyses showed sixty-five characteristic ion peaks which could be more efficient to assignment the aglycones and fragmentation sequences of sugar moieties. The used ionization modes provided consistent and/or complementary information for most of the pregnane glycosides, their fragmentation sequences, and their aglycones. A DFT Study was performed to elucidate the neutral loss of H2O molecules sequences from aglycones and the esterification linkage.This report could be useful to reduce material consuming and time in phytochemistry analysis of the different medicinal plants. The two portions significantly depleted TBARS were subjected to autoperoxidation assay in the presence of hydrogen peroxide.

Polyoxypregnane Ester Derivatives and Lignans from Euphorbia gossypina var. coccinea Pax.

From the aerial parts of Euphorbia gossypina var. coccinea Pax., eight new pregnane glycosides (euphogossypins A–H, 1–8) of the cynanforidine and deacetylmetaplexigenin aglycons, two new lignans (gossypilignans A and B, 9 and 10), and four known compounds, namely, the pregnane 12-O-benzoyldeaxcylmetaplexigenin (11), the lignan 9α-hydroxypinoresinol (12), and the flavonoids naringenin (13) and quercitrin (14) were isolated. The structure elucidation of the new compounds was carried out by a spectroscopic analysis, including HRMS, 1D (1H, 13C JMOD), and 2D NMR (HSQC, 1H–1H COSY, HMBC, and NOESY) experiments. The obtained pregnane glycosides were substituted with acetyl and benzoyl ester moieties, and sugar chains containing thevetose, cymarose, digitoxose, and glucose monosaccharides. All of the compounds are described for the first time from E. gossypina var. coccinea. The isolated pregnanes and lignans were tested for their antiproliferative activity on HeLa cells using the MTT assay; the compounds exerted no significant effect against the tumor cells.

Russelioside B: a Pregnane Glycoside with Pharmacological Potential.

Pregnanes and pregnane glycosides or their esters are well-studied secondary metabolites, many of them exhibit immunomodulator, anticancer, antidiabetic, antarthritic, antiulcer, anti-nociceptive, hypolipidemic, anti-inflammatory, and antibacterial properties. Pregnane glycosides are widely distributed in the families Apocyanaceae and Asclepiadaceae. Plant members of the genus Caralluma R.Br., Apocynaceae, are among the most studied species because of uses in traditional medicine or as food. They are a rich source of pregnane glycosides, as russelioside B. However, the bioactivity profile of this pregnane glycoside has not been reviewed until now. The present review aims to summarize the most important pharmacological and therapeutic applications of russelioside B with specific emphasis on the mechanism of actions associated with its administration in preclinical models. Russelioside B has many pharmacological effects including antidiabetic, anti-obesity, anti-nociceptive, antiulcer, anti-inflammatory, anti-arthritis effects, and antibiofilm, and wound healing activities. Despite its outstanding pharmacotherapeutic potential, russelioside B has never been tested in clinical trials. This review indicates that russelioside B is a potentially promising bioactive candidate, but further deeper mechanistic studies and clinical trials are needed in the future to elucidate its interaction with receptors of specific genes.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s43450-022-00245-x.

Iloneoside, an antimalarial pregnane glycoside isolated from Gongronema latifolium leaf, potentiates the activity of chloroquine against multidrug resistant Plasmodium falciparum

The rapid spread of drug resistant malaria parasites has necessitated the search for novel antimalarials and chemosensitizers capable of reversing drug resistance in the parasites. A number of studies have revealed the resistance reversal activities of pregnane glycosides and the antimalarial activity of a pregnane glycoside obtained from Gongronema species. However, the pregnane (2) and pregnane glycosides (1, 3–4) isolated from Gongronema latifolium leaf have not been evaluated for these activities. This study was therefore carried out to evaluate the antiplasmodial and chloroquine resistance reversal activities of a pregnane and three pregnane glycosides isolated from G. latifolium leaf in vitro. The compounds were evaluated for their inhibitory activities against P. falciparum 3D7 (a chloroquine-sensitive strain) and P. falciparum W2 (a chloroquine-resistant clone) in vitro. The activities of chloroquine in separate combination with each of the compounds against P. falciparum W2 were also evaluated. Moreover, the interaction of the active compounds (1 and 4) with selected P. falciparum proteins (PfProteins) were evaluated in silico. The results revealed that only 1 and 4 were active against P. falciparum 3D7 and P. falciparum W2. Also, 2 and 3 did not exhibit chloroquine resistance reversal activity. Activity of chloroquine against P. falciparum W2 was potentiated by 1 by 3200% at concentrations higher than 0.625 µg/mL. Also, 1 and 4 demonstrated similar binding patterns and higher binding tendencies to the selected PfProteins compared to chloroquine. Thus, 1 (iloneoside) is an antimalarial pregnane glycoside which can potentiate the activity of chloroquine against multidrug resistant P. falciparum.

Cytotoxic triterpene and steroidal glycosides from the seeds of Digitalis purpurea and the synergistic cytotoxicity of steroidal glycosides and etoposide in SBC-3 cells

The phytochemical investigations of the seeds of Digitalis purpurea have revealed their richness in cardenolide and pregnane glycosides exhibiting potent cytotoxicity; further chemical examinations of the D. purpurea seeds have achieved the isolation of six triterpene glycosides (1–6), six spirostanol glycosides (7–12), and three furostanol glycosides (13–15), including seven previously unidentified compounds (1–3, 10–12, and 14). Here, the structures of 1–3, 10–12, and 14 were determined via extensive spectroscopic analyses, including two-dimensional (2D) NMR; hydrolysis, followed by chromatographic and spectroscopic analyses; and X-ray crystallographic analysis. The cytotoxic activities of the isolated compounds (1–15) against SBC-3 small cell lung carcinoma and TIG-3 normal human diploid fibroblast cells were evaluated. Triterpene glycoside 3 and spirostanol glycoside 9 exhibited considerable cytotoxicity with IC50 values of 1.0 and 1.7 µM, respectively; they induced apoptotic cell death, which was accompanied by the activation of caspase-3 in SBC-3 cells. Spirostanol glycoside 7 exhibited cytotoxicity toward the SBC-3 cells (IC50 1.3 μM). Additionally, 7 at 0.1 and 1.0 µM synergistically enhanced the cytotoxicity of etoposide against SBC-3 cells; compound 7 induced the release of DAMPs; the release of HMGB1, the secretion of ATP, and the exposure of CALR in the SBC-3 cells. Furthermore, the combination of 7 and etoposide resulted in increasing the extracellular release of DAMPs. These data indicated that 7, as well as its combination with etoposide, might potentially cause immunogenic cell death.

Review on Pregnane Glycosides and Their Biological Activities

• Review on 345 Pregnane Glycosides and their biological activities. • The pregnane glycosides are classified into two major types based on linkages. • Pregnane glycosides have antitumor activity in recent years. Pregnane glycosides are exist in Asclepiadaceae , Apocynaceae , Malpighiaceae , Ranunculaceae and Zygophyllaceae . This is a class of substances with steroids as the mother nucleus and containing a glyosidic bond structure. Modern pharmacology has shown that these compounds are a class of compounds with different structures and multiple biological activities. It has a good development prospect in anti-cancer and anti-tumor directions. This article reviews the chemical structures and biological activities of 345 compounds from 1984 to 2019.

Cytotoxic polyhydroxylated pregnane glycosides from Cissampelos pareira var. hirsuta.

Fourteen new polyhydroxylated pregnane glycosides, cissasteroid A–N (1–14), and five known analogues (15–19), were isolated from the dried whole plant of Cissampelos pareira var. hirsuta. Their structures and stereochemistry were elucidated by extensive spectroscopic data, chemical hydrolysis, and ECD measurements. All the compounds were tested for their cytotoxicity against five human cancer cell lines, and inhibitory activity against NO release in LPS-induced RAW 264.7 cells. Compared with cisplatin, compound 7 showed more potent cytotoxicities against the HL-60, A549, SMMC-7721, MCF-7, and SW480 cell lines, with IC50 values of 2.19, 14.38, 2.00, 7.58, and 7.44 μM, respectively. The preliminary study of structure–activity relationship indicated that benzoic acid esterification at C-20 may have a negative effect on the cytotoxic activity of polyhydroxylated pregnane derivatives in these five human cancer cell lines. These results revealed the potential of compound 7 as an ideal antitumor lead compound.

Pregnane glycosides from Adonis amurensis and their bioactivity

Seven undescribed pregnane glycosides named amurensides A–G and two known aglycones were isolated from the whole herb of Adonis amurensis Regel & Radde. Their structures were established based on 1D and 2D NMR spectroscopic analyses, high-resolution mass spectrometry, and acid hydrolysis. The cytotoxicity of all compounds against three tumor cell lines (HepG2, Caco-2, and A549) were evaluated. Among them, amurensides A–C and E showed moderate inhibitory effects on the growth of HepG2 cells, with IC50 values ranging from 15.6 to 48.7 μM (sorafenib, 7.5 ± 1.9 μM). Amurensides A、D and F displayed inhibitory effects on the growth of A549 cells with IC50 values of 18.8 ± 1.2, 12.4 ± 0.6, and 30.4 ± 0.1 μM (cis-platinum, 6.1 ± 0.1 μM), respectively.

New Pregnane Glycosides Isolated from Caralluma hexagona Lavranos as Inhibitors of α-Glucosidase, Pancreatic Lipase, and Advanced Glycation End Products Formation.

Caralluma hexagona Lavranos (Family Asclepiadaceae) is an endemic herb in Yemen and Saudi Arabia, traditionally used to treat diabetes, abdominal pain, and stomach ulcers. Different extracts, fractions, and main constituents of C. hexagona were evaluated for their inhibitory activity against key enzymes in diabetes and hyperlipidemia, i.e., α-glucosidase and pancreatic lipase. In addition, the antioxidative effect and inhibition of advanced glycation end products (AGEs) were also assayed. Using a bioguided approach, the crude aqueous, methanolic extracts, methylene chloride (CH2Cl2), Diaion HP20 50% MeOH (DCF-1), and 100% MeOH (DCF-2) fractions of C. hexagona were evaluated for their possible α-glucosidase and pancreatic lipase inhibition and antioxidant activity. In addition, inhibition of AGE generation using bovine serum albumin (BSA)-fructose, BSA-methylglyoxal, and arginine-methylglyoxal models was carried out. Moreover, the main constituents of the most active fraction were isolated and identified using different chromatographic and sprectroscopic methods. From the most active CH2Cl2 fraction, four new pregnane glycosides were isolated and identified as 12β-O-benzoyl 3β,8β,12β,14β,20-pentahydroxy-(20S)-pregn-5-ene-3-O-β-d-glucopyranosyl-(1 → 4)-O-β-d-digitaloside (1), 3β,8β,14β,20-tetrahydroxy-(20S)-pregn-5-ene-3-O-β-d-glucopyranosyl-(1 → 4)-O-β-d-digitaloside-20-O-3-isoval-β-d-glucopyranoside (2), 3β,8β,14β,20-tetrahydroxy-(20R)-pregn-5-ene-3-O-β-d-glucopyranosyl-(1 → 4)-O-β-d-digitaloside-20-O-3-isoval-4-benzoyl-β-d-glucopyranoside (3A), and 3β,8β,14β,20-tetrahydroxy-(20R)-pregn-5-ene-3-O-β-d-glucopyranosyl-(1 → 4)-O-β-d-digitaloside-20-O-3,4 di-benzoyl-β-d-glucopyranoside (3B). Among the tested samples, the highest trolox equivalent (TE) antioxidant capacity (TEAC) was observed for DCF-1 with values of 128.53 ± 5.07, 378.58 ± 5.19, and 106.71 ± 5.66 μM TE/mg using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and ferric reducing antioxidant potential (FRAP) assays, respectively. The isolated apigenin-8-C-neohesperoside showed the highest antioxidant capacity (168.80 ± 1.80 and 278.21 ± 13.26 μM TE/mM) in DPPH and FRAP, respectively, while luteolin 4′-O-β-d-neohesperidoside had the highest TEAC (599.19 ± 9.57 μM TE/mM) in ABTS assay. Compounds 1, 2, and the mixture 3A and 3B inhibited α-glucosidase with IC50 values of 0.92 ± 0.02, 0.67 ± 0.01, and 0.74 ± 0.02 mM, respectively. In the AGE assays, DCF-1 showed the highest inhibitory effect in BSA-fructose and arginine-methylglyoxal models with IC50 values of 0.39 ± 0.02 and 0.77 ± 0.10 mg/mL, respectively. Among the isolated compounds, flavonoid compounds showed the highest antiglycation effect, while pregnanes revealed higher α-glucosidase inhibition. In conclusion, the current study revealed that C. hexagona is a promising Yemeni natural remedy, of which the major content of pregnane glycosides and flavonoids could be considered as a new therapeutic candidate targeting the metabolic syndrome.