Search Results (80)

In this report, we describe the synthesis and full spectroscopic characterization of a previously unreported podophyllotoxin (PTOX) analogue bearing a second 3,4,5-trimethoxyphenyl (TMP) unit at the C-4 position through an ester linkage. This dual-TMP PTOX derivative is obtained from a brominated PTOX intermediate. In this precursor, the bromine atom is located on the TMP aromatic ring at the 2′-position. The new compound was fully characterized by proton (¹H), carbon-13 (¹³C), heteronuclear single-quantum coherence (HSQC), and distortionless enhancement by polarization transfer (DEPT) NMR spectroscopy. Ultraviolet–visible (UV-Vis) spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, mass spectrometry and elemental analysis were also performed to confirm the structure and purity of the synthesized ester derivative. Full article

In the third edition of this Special Issue, the participating researchers focused their studies on bispecific antibodies against solid tumors [contribution 1], teratoma development [contribution 2], the seminoma microenvironment [contribution 3], neuroblastoma and peptidergic systems [contribution 4], hepatocellular carcinoma [contribution 5], the synthesis of novel podophyllotoxin–benzothiazole congeners for use as anticancer agents [contribution 6], the effects of podophyllotoxin derivatives on non-cancerous diseases [contribution 7], and the involvement of the aryl hydrocarbon receptor and the signal transducer and activator of transcription 3 in chemical carcinogenesis [contribution 8] [...] Full article

Vulvar viral infections such as condyloma acuminata, genital herpes, molluscum contagiosum, and Lipschütz ulcers span both sexually and non-sexually transmitted diseases and affect patients across all age groups. Lesions may present as papules, verrucous growths, or painful ulcers, often causing functional impairment and significant psychosocial distress. A multidisciplinary strategy that integrates epidemiology, precise diagnostics, individualized therapy, and psychological support is essential to optimize outcomes. We performed a structured literature search in PubMed, Scopus, and Web of Science using terms “vulvar viral infection,” “HPV,” “HSV,” “molluscum contagiosum,” and “Lipschütz ulcers.” International guidelines from the UK, Europe, and Australia were reviewed, alongside reference lists of key articles. Particular attention was given to paradoxical presentations, pediatric considerations, and cost-effectiveness analyses. HPV vaccination programs have markedly reduced anogenital warts, while early PCR/NAAT for HSV accelerates targeted antiviral therapy. First-line treatments like oral acyclovir/famciclovir for HSV and topical imiquimod or podophyllotoxin (±cryotherapy) for HPV are supported by adjunctive measures for self-limiting conditions. Host factors (hormonal cycles, immune status) and local irritants modulate recurrence risk, informing anticipatory suppressive regimens and barrier-reinforcing care. Validated patient-reported outcome measures (VPAQ, DLQI, FSFI) capture pain, sexual function, and quality-of-life impacts. Health–economic evaluations underscore the long-term value of rapid diagnostics and broad vaccination. Personalized, multidisciplinary management that combines prevention, precision diagnostics, tailored therapy, psychosocial support, and economic considerations offers the greatest promise for improving clinical and quality-of-life outcomes in patients with vulvar viral infections. We aim to outline best practices for the diagnosis and management of common vulvar viral infections, providing practical guidance for clinicians to improve recognition and therapeutic decision-making. Full article

A series of novel podophyllotoxin derivatives containing benzothiazole scaffolds were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (MCF-7, SKOV-3, B16F10, LOVO, and HeLa). Two compounds, 7 and 11, which are different only by the absence or presence of the ester group, showed the strongest cytotoxic effect towards all tested cancer cell lines with the IC₅₀ 0.68–2.88 µM. In addition, it was demonstrated that these compounds inhibit cancer cell proliferation by inducing G2/M phase arrest in HeLa cells. The structure–activity relationship was analyzed and it confirmed the importance of the core structural features like a dioxolane ring and free-rotating trimethoxyphenyl group for cytotoxicity. Moreover, the R configuration of the ester group at the C-8′ position proved to be substantial since its epimer was inactive. The molecular docking studies revealed that the most potent compounds have a different binding mode to β-tubulin than podophyllotoxin; however, the benzothiazole fragment docked in a similar location as the trimethoxyphenyl group of podophyllotoxin, exhibiting similar hydrophobic interactions. These findings clearly indicate that podophyllotoxin–benzothiazole derivatives could be addressed for further pharmacological studies in anticancer research. Full article

Nanotechnology offers alternative approaches to the discovery of anticancer drugs. Hydrophobic bioactive components can be included in the cores of amphiphilic nanocarriers, which leads to the formation of a water-dispersible product with improved bioavailability, facilitated excretion, and reduced systemic toxicity in the treated organisms. This study was aimed at the formation of polymer nanocarriers, loaded with anticancer drug precursor podophylotoxin (PPT) or PPT-containing juniper leaf extracts, seeking to study their antineoplastic activity in A-431 epidermoid carcinoma cells and HaCaT normal keratinocytes. The amphiphilic, biodegradable, and biocompatible MPEG-b-PLA diblock copolymer was self-assembled in aqueous media into nanosized particles, whose physicochemical characteristics were studied by dynamic light scattering, transmission electron microscopy, and other methods. High encapsulation efficiency was determined for the PPT component-loaded micelles. DNA fragmentation, cell cycle arrest, nuclear condensation, membrane lipid order assessment, reactive oxygen species, and apoptosis induction by the loaded nanocarriers in A-431 or HaCaT cells were analyzed by the comet assay, FACS, Hoechst DNA staining, Laurdan generalized polarization, and other methods. As a result of various cellular processes induced by the PPT component-loaded nanoparticles, effector caspase-3 and caspase-7 activation showed selectivity towards tumor cells compared to the normal cells. The newly obtained PPT-containing nanoparticles have applications as potential drugs in the prospective nanomedicine. Full article

In cytogenetics, the ability to perform FISH (Fluorescence In Situ Hybridization) experiments using probes that map very closely together depends on the capacity to produce sufficiently long chromosomes. Traditionally, colcemid is the chemical agent used to obtain metaphase spreads. However, various substances have been reported to arrest cells in an earlier stage of mitosis than the metaphase, potentially providing longer chromosomes. In this study, we tested seven substances different from colcemid, which, according to the literature, have this capability: Vinblastine, Combretastatin A-4, Podophyllotoxin, Org9935, Nocodazole, Paclitaxel, and Griseofulvin. All substances were tested on lymphocyte cultures derived from whole blood at the same concentration: 0.1 µg/mL. Among these, Org9935 and Griseofulvin were confirmed to have the ability to produce metaphases with longer chromosomes compared to those obtained with colcemid. Full article

Background: Condyloma acuminata (CA) are dysplastic lesions caused by human papillomavirus (HPV) infection. Condylomata acuminata are common in Human Immunodeficiency Virus- (HIV) infected individuals and have been linked to HIV transmission. Current therapeutic options for CA encompass laser, cryotherapy, imiquimod, sinecatechins, podophyllotoxin, and trichloroacetate. These topical therapies have limitations caused by significant local skin reactions, high recurrence rates, prolonged application times, and, in some cases, a supposed lower efficacy in people living with Human Immunodeficiency Virus (PLWH). Previous studies evaluated the effect in the CA treatment of tirbanibulin 1% ointment since it is a synthetic antiproliferative drug approved for the topical treatment of actinic keratoses, acting in two distinct ways: it inhibits microtubule polymerization and Src kinase signaling. Human papilloma virus can up-regulate the kinases Src and Yes, so the tirbanibulin efficient treatment of CA may be due to the suppression of Src kinase signaling. Methods: Here, we present for the first time a retrospective case series of three PLWHIV affected by CA. Case: The patients experienced variable outcomes, with complete resolution of smaller condylomas for 2 out of 3 patients. Adverse events were local and of mild to moderate severity, lasting one week or less. Conclusions: While in need of larger studies, it is possible to hypothesize tirbanibulin 1% ointment as a therapeutic alternative for people living with HIV, especially for condylomas smaller than 1 cm in size. Full article

Sinopodophyllum hexandrum (Royle) Ying, the only species of Sinopodophyllum in Berberidaceae, is an endangered traditional Tibetan medicine. The harsh plateau growth environment makes S. hexandrum tough to breed and meet the global demand for clinical medications such as podophyllotoxin (PTOX) and etoposide. Jasmonic acid (JA) is acknowledged as a key phytohormone that modulates stress responses by activating defense mechanisms and promoting the production of specialized metabolites, which offers valuable insights for developing varieties that are more resilient to stress or yield higher amounts of secondary metabolites. In this study, JA treatment was used as a simulated source of stress to investigate the spatiotemporal changes in phytohormones, such as JA, cis-(+)-12-oxo-10, 15(Z)-phytodienoic acid (cis-(+)-OPDA), and abscisic acid (ABA), and transcriptional regulation following hormonal regulation in intact plants. Some correlations through changes in phytohormone levels and the expression level of related signaling pathway genes were observed to confirm the overall regulatory effect after the JA treatment. Furthermore, the JA treatment caused the differential expression of various genes including transcription factors (TFs), of which the most typical one is myelocytomatosis oncogene like protein 2 (MYC2), ShMYC2_3. Therefore, we proposed that a plant hormone-mediated regulatory network exists endogenously in S. hexandrum, enabling it to respond to JA treatment. This study provides a new direction for the germplasm improvement and the sustainable utilization of S. hexandrum when facing exogenous stimulation. Full article

Podophyllotoxin is a natural compound belonging to the lignan family and is well-known for its great antitumor activity. However, it shows several limitations, such as severe side effects and some pharmacokinetics problems, including low water solubility, which hinders its application as an anticancer agent. Over the past few years, antitumor research has been focused on developing nanotechnology-based medicines or nanomedicines which allow researchers to improve the pharmacokinetic properties of anticancer compounds. Following this trend, podophyllotoxin nanoconjugates have been obtained to overcome its biopharmaceutical drawbacks and to enhance its antitumor properties. The objective of this review is to highlight the advances made over the past few years (2017–2023) regarding the inclusion of podophyllotoxin in different nanosystems. Among the huge variety of nanoconjugates of diverse nature, drug delivery systems bearing podophyllotoxin as cytotoxic payload are organic nanoparticles mainly based on polymer carriers, micelles, and liposomes. Along with the description of their pharmacological properties as antitumorals and the advantages compared to the free drug in terms of biocompatibility, solubility, and selectivity, we also provide insight into the synthetic procedures developed to obtain those podophyllotoxin-nanocarriers. Typical procedures in this regard are self-assembly techniques, nanoprecipitations, or ionic gelation methods among others. This comprehensive perspective aims to enlighten the medicinal chemistry community about the tendencies followed in the design of new podophyllotoxin-based drug delivery systems, their features and applications. Full article

Podophyllotoxin (PPT) is commonly used for genital warts due to its antimitotic properties and relatively good accessibility since it can be extracted from plants in low-economy countries. However, due to relatively high toxicity, it cannot be used in a systematic way (intravenously). Thus, there is a need to find or create an equally effective derivative of PPT that will be less toxic. Natural PPT is a suitable and promising scaffold for the synthesis of its derivatives. Many of them have been studied in clinical and preclinical models. In this systematic review, we comprehensively assess the medical applications of PPT derivatives, focusing on their advantages and limitations in non-cancerous diseases. Most of the existing research focuses on their applications in cancerous diseases, leaving non-cancerous uses underexplored. To do that, we systematically reviewed the literature using PubMed, Embase, and Cochrane databases from January 2013 to January 2025. In total, 5333 unique references were identified in the initial search, of which 44 were included in the quantitative synthesis. The assessment of the quality of eligible studies was undertaken using the PRISMA criteria. The risk of bias was assessed using a predefined checklist based on PRISMA guidelines. Each study was independently reviewed by two researchers to evaluate bias in study design, reporting, and outcomes. Our analysis highlights the broad therapeutic potential of PPT derivatives, particularly in antiviral applications, including HPV, Dengue, and SARS-CoV-2 infections. Apart from their well-known anti-genital warts activity, these compounds exhibit significant anti-inflammatory, antimitotic, analgesic, and radioprotective properties. For instance, derivatives such as cyclolignan SAU-22.107 show promise in antiviral therapies, while compounds like G-003M demonstrate radioprotective effects by mitigating radiation-induced damage. To build on this, our review highlights that PPT derivatives, apart from anti-genital warts potential, exhibit four key properties—anti-inflammatory, antimitotic, analgesic, and radioprotective—making them promising candidates not only for treating viral infections such as HPV, Dengue, and SARS-CoV-2 but also for expanding their therapeutic potential beyond cancerous diseases. In conclusion, while PPT derivatives hold great potential across various medical domains, their applications in non-cancerous diseases remain limited by the scarcity of dedicated research. Continued exploration of these compounds is essential to unlock their full therapeutic value. Full article

The tumor-suppressor sphingolipid ceramide is recognized as a key participant in the cytotoxic mechanism of action of many types of chemotherapy drugs, including anthracyclines, Vinca alkaloids, the podophyllotoxin etoposide, taxanes, and the platinum drug oxaliplatin. These drugs can activate de novo synthesis of ceramide or stimulate the production of ceramide via sphingomyelinases to limit cancer cell survival. On the contrary, dysfunctional sphingolipid metabolism, a prominent factor in cancer survival and therapy resistance, blunts the anticancer properties of ceramide-orchestrated cell death pathways, especially apoptosis. Although P-glycoprotein (P-gp) is famous for its role in chemotherapy resistance, herein, we propose alternate interpretations and discuss the capacity of this multidrug transporter as a “ceramide neutralizer”, an unwelcome event, highlighting yet another facet of P-gp’s versatility in drug resistance. We introduce sphingolipid metabolism and its dysfunctional regulation in cancer, present a summary of factors that contribute to chemotherapy resistance, explain how P-gp “neutralizes” ceramide by hastening its glycosylation, and consider therapeutic applications of the P-gp-ceramide connection in the treatment of cancer. Full article

Podophyllum hexandrum Royle, also known as Podophyllum emodi Wall, holds significant ecological, ornamental, and medicinal values. However, it has become endangered due to overexploitation, prolonged seed dormancy, slow natural regeneration, and climate change. This study developed an efficient in vitro protocol for callogenesis and micropropagation of P. hexandrum to conserve germplasm in in vitro conditions. Callus formation from various plant parts, including the leaf, stem, rhizome, radicle, and cotyledon, was induced using Murashige and Skoog (MS) medium supplemented with different plant growth regulators. The combination of benzyladenine at 1 mg L⁻¹ and 4-dichlorophenoxy acetic acid at 3 mg L⁻¹ was optimal for biomass production, yielding 215.88 ± 0.31 mg, with growth per gram at 8.32 ± 0.32 and a growth rate of 13.62 ± 0.25 mg/day on MS medium. For shoot proliferation, benzyladenine (3.5 mg L⁻¹) and naphthalene acetic acid (0.5 mg L⁻¹) combined with activated charcoal showed the highest shoot induction percentage per explant. For shoot regeneration from calluses, 6-benzylaminopurine (0.5 mg L⁻¹) and thidiazuron (2 mg L⁻¹) were most effective, producing superior shoot length, number of regenerations, and regeneration percentage. Root induction was successful with α-naphthalene acetic acid supplementation (0.5 to 1.5 mg L⁻¹) in MS medium, resulting in the highest number per explant (4.08 ± 0.08), length (5.45 ± 0.15 cm), and rooting rate (87.00 ± 1.66%) of roots in plantlets. Subculturing for callus culture was performed every 28 days for up to four subcultures to prevent nutrient depletion and toxic metabolite accumulation, ensuring tissue health and viability. Continuous subculturing of callus on MS medium maintained healthy P. hexandrum germplasm in vitro. Overall, this micropropagation protocol provides a rapid system for conserving P. hexandrum germplasm. Full article

Bursera fagaroides, popularly used in México, possesses bioactive lignans. These compounds are low in the bark, and its extraction endangers the life of the trees. The aim of the present investigation was to search for alternative sources of cytotoxic compounds in B. fagaroides prepared as leaves and in vitro callus cultures. The friable callus of B. fagaroides was established using a combination of plant growth regulators: 4 mgL⁻¹ of 2,4-dichlorophenoxyacetic acid (2,4-D), 1 mgL⁻¹ Naphthaleneacetic Acid (NAA) and 1 mgL⁻¹ Zeatin. The maximum cell growth was at day 28 with a specific growth rate of μ = 0.059 days⁻¹ and duplication time td = 11.8 days. HPLC quantification of the dichloromethane callus biomass extract showed that Scopoletin, with a concentration of 10.7 µg g⁻¹ dry weight, was the main compound inducible as a phytoalexin by the addition of high concentrations of 2,4-D, as well as by the absence of nutrients in the culture medium. In this same extract, the compounds γ-sitosterol and stigmasterol were also identified by GC-MS analysis. Open column chromatography was used to separate and identify yatein, acetyl podophyllotoxin and 7′,8′-dehydropodophyllotoxin in the leaves of the wild plant. Cytotoxic activity on four cancer cell lines was tested, with PC-3 prostate carcinoma (IC₅₀ of 12.6 ± 4.6 µgmL⁻¹) being the most sensitive to the wild-type plant extract and HeLa cervical carcinoma (IC₅₀ of 72 ± 5 µgmL⁻¹) being the most sensitive to the callus culture extract. Full article

Podophyllotoxin (PPT) is an active pharmaceutical ingredient (API) with established antitumor potential. However, due to its systemic toxicity, its use is restricted to topical treatment of anogenital warts. Less toxic PPT derivatives (e.g., etoposide and teniposide) are used intravenously as anticancer agents. PPT has been exploited as a scaffold of new potential therapeutic agents; however, fewer studies have been conducted on the parent molecule than on its derivatives. We have undertaken a study of ultrastructural changes induced by PPT on HaCaT keratinocytes. We have also tracked the intracellular localization of PPT using its fluorescent derivative (PPT-FL). Moreover, we performed molecular docking of both PPT and PPT-FL to compare their affinity to various binding sites of tubulin. Using the Presto blue viability assay, we established working concentrations of PPT in HaCaT cells. Subsequently, we have used selected concentrations to determine PPT effects at the ultrastructural level. Dynamics of PPT distribution by confocal microscopy was performed using PPT-FL. Molecular docking calculations were conducted using Glide. PPT induces a time-dependent cytotoxic effect on HaCaT cells. Within 24 h, we observed the elongation of cytoplasmic processes, formation of cytoplasmic vacuoles, progressive ER stress, and shortening of the mitochondrial long axis. After 48 h, we noticed disintegration of the cell membrane, progressive vacuolization, apoptotic/necrotic vesicles, and a change in the cell nucleus’s appearance. PPT-FL was detected within HaCaT cells after ~10 min of incubation and remained within cells in the following measurements. Molecular docking confirmed the formation of a stable complex between tubulin and both PPT and PPT-FL. However, it was formed at different binding sites. PPT is highly toxic to normal human keratinocytes, even at low concentrations. It promptly enters the cells, probably via endocytosis. At lower concentrations, PPT causes disruptions in both ER and mitochondria, while at higher concentrations, it leads to massive vacuolization with subsequent cell death. The novel derivative of PPT, PPT-FL, forms a stable complex with tubulin, and therefore, it is a useful tracker of intracellular PPT binding and trafficking. Full article

When new antitumor therapy drugs are discovered, it is essential to address new target molecules from the point of view of chemical structure and to carry out efficient and systematic evaluation. In the case of natural products and derived compounds, it is of special importance to investigate chemomodulation to further explore antitumoral pharmacological activities. In this work, the compound podophyllic aldehyde, a cyclolignan derived from the chemomodulation of the natural product podophyllotoxin, has been evaluated for its viability, influence on the cell cycle, and effects on intracellular signaling. We used functional proteomics characterization for the evaluation. Compared with the FDA-approved drug etoposide (another podophyllotoxin derivative), we found interesting results regarding the cytotoxicity of podophyllic aldehyde. In addition, we were able to observe the effect of mitotic arrest in the treated cells. The use of podophyllic aldehyde resulted in increased cytotoxicity in solid tumor cell lines, compared to etoposide, and blocked the cycle more successfully than etoposide. High-throughput analysis of the deregulated proteins revealed a selective antimitotic mechanism of action of podophyllic aldehyde in the HT-29 cell line, in contrast with other solid and hematological tumor lines. Also, the apoptotic profile of podophyllic aldehyde was deciphered. The cell death mechanism is activated independently of the cell cycle profile. The results of these targeted analyses have also shown a significant response to the signaling of kinases, key proteins involved in signaling cascades for cell proliferation or metastasis. Thanks to this comprehensive analysis of podophyllic aldehyde, remarkable cytotoxic, antimitotic, and other antitumoral features have been discovered that will repurpose this compound for further chemical transformations and antitumoral analysis. Full article