resveratrol [ 57 ], piceatannol [ 10 ], pterostilbene [ 61, 62, 63 ], and polydatin ( piceid ) [ 64 ] were reported to suppress the proliferation of various cancer cell lines ( lung, prostate, breast, colorectal, liver, pancreatic, cervical, ovarian, bladder, leukemia, multiple myeloma, bone, oral, esophageal, head and neck ). regarding the impact of resveratroloside ( 1 ) and pinostilbenoside ( 2 ) on the hela cell cycle, both compounds induced a significant dose - dependent increase in the sub - g1 phase population. in addition, both compounds ( 25 μg / ml ) induced cell cycle arrest at the s phase, indicating a blockage of dna replication [ 60 ]. as mentioned earlier, the sub - g1 population is a hallmark of apoptosis [ 39, 40 ]. in fact, not only apoptotic cells accumulate in the sub - g1 phase, but this phase consists of cells showing dna fragmentation, a process observed in both apoptosis and necrosis [ 65, 66, 67 ]. when exploring a potential pro - apoptotic effect, only resveratroloside ( 1 ) showed activity ( approximately 11 % increase in the early and late apoptotic hela cells following 48 h treatment with resveratroloside ( 1 ) at 50 μg / ml ). the results of this study indicate that resveratroloside ( 1 ) and pinostilbenoside ( 2 ) impact the viability and proliferation of hela cells by triggering mainly non - apoptotic ( highly likely necrotic ) cell death, as well as s-phase cell cycle arrest. similar results have been reported for other stilbene derivatives. resveratrol was found to induce apoptosis and block cell cycle progression in the s phase in human sw480 colon carcinoma, mcf7 breast carcinoma, hce7 esophageal squamous carcinoma, hl60 promyelocytic leukemia cells [ 68 ], and neuro - 2a cells derived from c1300 murine neuroblastoma [ 69 ]. piceatannol caused apoptosis and g0 / g1 phase arrest in t24 and ht1376 human bladder cancer cells [ 70 ]. pterostilbene was reported to induce apoptosis and s-phase arrest in molt4 human leukemia cells [ 71 ], jurkat and hut - 78 t - cell leukemia / lymphoma cells [ 72 ], and diffuse large b - cell lymphoma cells [ 73 ], apoptosis and g1 phase arrest in ht - 29 colon cancer cells [ 58 ] and human gastric carcinoma ags cells [ 74 ], and autophagy and s phase arrest in hccc - 9810 and rbe human cholangio carcinoma cells [ 62 ]. to conclude the cytotoxicity assays, resveratroloside ( 1 ) and pinostilbenoside ( 2 ) reduced viability ( mostly via non - apoptotic routes ) and proliferation ( via sub - g1 - and s-phase arrest ) in hela cells. the results are consistent with previous studies on the antitumor potential of stilbenes. resveratrol, the basic scaffold of resveratroloside ( 1 ) and pinostilbenoside ( 2 ), was reported to promote cell cycle arrest at the s phase, apoptosis, and autophagy in hela cells [ 52 ]. polydatin, a glyco side of resveratrol, namely resveratrol - 3 - o - β - mono - d - glucoside, reduced proliferation and induced apoptosis in hela cells [ 64 ]. in this study, resveratroloside ( 1 ) and pinostilbenoside ( 2 ) exhibited comparable activity in arresting the hela cell cycle at the s and sub - g1 phases ( at 25 and 50 μg / ml, respectively ). on the other hand, pinostilbenoside ( 2 ) exhibited higher activity than resveratroloside ( 1 ) in increasing the number of dead cells through non - apoptotic mechanisms ( at 25 and 50 μg / ml ) and in reducing hela cell proliferation ( at 25 μg / ml ). the latter findings are consistent with earlier studies reporting increased cytotoxic activity for the methoxylated analogs of resveratrol compared to resveratrol itself [ 75 ]. the two compounds ( 1 and 2 ) isolated in this study are stilbene glyco sides. glyco sylation is known to positively impact the water solubility, intestinal absorption, and bioactivity of stilbenes [ 76, 77 ]. a notable example is polydatin, one of the main compounds in the roots of polygonum cuspidatum sieb. et zucc., identified in other plant species across the liliaceae, fabaceae, and vitaceae families. based on its anti-inflammatory, antioxidant, and apoptosis - modulating potential, polydatin displays diverse biological activities ( anticancer, antidiabetic, antimicrobial, cardioprot ective, hepatoprotective, and neuroprotective effects, as well as protective effects on the gastrointestinal, renal, respiratory, and skeletal systems ). a large number of studies conducted on polydatin has revealed versatility in modulating numerous targets related to oxidative stress ( nrf2 and akt pathways, glutathione, catalase ( cat ), sod, gpx, gst, mpo ), inflammation ( nf - κb, phospholipase a2 ( pla2 ), cox - 2, inos, tnf - α, il - 1β, il - 6, icam - 1, mapks, erk1 / 2, jnk1 / 2 ), and apoptosis ( p53 / mapk / jnk and pi3k / akt / mtor pathways, b - cell lymphoma 2 ( bcl - 2 ), bcl - 2 - associated x ( bax ), d - cyclins, caspase - 3, cytochrome c ). clinical trials support the benefits of polydatin in chronic pelvic pain, liver diseases, inflammatory bowel syndrome, and egfr - tyrosine kinase inhibitor ( tki ) - related ashes. moreover, various drug delivery systems ( liposomes, micelles, nanoparticles, polymeric nanocapsules ) have been developed to improve the bioavailability, biocompatibility, and efficacy of polydatin [ 64, 78 ]. the results of the present study, along with the remarkable biological potential of the stilbene scaffold and the broad bioactivity of polydatin, a resveratrol glyco side, indicate that the bioactive properties of resveratroloside ( 1 ) and pinostilbenoside ( 2 ) require further in - depth investigation. future studies should explore the ability of resveratroloside ( 1 ) and pinostilbenoside ( 2 ) to modulate cellular signaling pathways, enzymes, and other molecules involved in the antioxidant defense and oxidative damage repair. research on the antitumor potential ( mechanisms underlying cytotoxic activity in hela cells, cytotoxicity against other tumor cell lines ) should also continue. exploration of additional bioactivities and development of appropriate delivery systems are crucial for the therapeutic valorization of resveratroloside ( 1 ) and pinostilbenoside ( 2 ). statistical analysis antioxidant assays were performed in triplic ate, and the results were expressed as mean ± standard deviation ( sd ). hela cell - based assays were performed in triplic ate; the results were expressed as mean ± standard error ( se ). the differences between the results were tested using one - way anova with tukey ’ s hsd test ( spss version 18. 0 ); conclusions * * * in this study, resveratroloside ( 1 ) and pinostilbenoside ( 2 ) were first isolated from pinus cembra l. bark. this is the first report of these compounds in this species. their structures were confirmed by 1h - nmr, 13c - nmr, and hresims. compared to the raw bark extract, resveratroloside ( 1 ) and pinostilbenoside ( 2 ) showed lower activity as free radical scavengers and reducing agents. however, they were more effective in reducing the viability and suppressing the proliferation of human cervical carcinoma hela cells. at 25 µg / ml, both compounds induced s-phase cell cycle arrest in hela cells. at 25 and 50 µg / ml, they significantly reduced the viability of hela cells, mainly through non - apoptotic mechanisms. glyco sylated stilbene scaffolds have great potential for therapeutic applications, so further studies are needed to assess the bioactive potential of resveratroloside ( 1 ) and pinostilbenoside ( 2 ).