Potential of cucurbitacin as an anticancer drug.

In Chinese medicine, the Cucurbitaceae family contains many compounds known as cucurbitacins, which have been categorized into 12 classes ranging from A to T and more than 200 derivatives. Cucurbitacins are a class of highly oxidized tetracyclic triterpenoids with potent anticancer properties. The eight components of cucurbitacins with the strongest anticancer activity are cucurbitacins B, D, E, I, IIa, L-glucoside, Q, and R. Cucurbitacins have also been reported to suppress JAK-STAT 3, mTOR, VEGFR, Wnt/ß-catenin, and MAPK signaling pathways, all of which are crucial for the survival and demise of cancer cells. In this paper, we review the progress in research on cucurbitacin-induced apoptosis, autophagy, cytoskeleton disruption, cell cycle arrest, inhibition of cell proliferation, inhibition of invasion and migration, inhibition of angiogenesis, epigenetic alterations, and synergistic anticancer effects in tumor cells. Recent studies have identified cucurbitacins as promising molecules for therapeutic innovation with broad versatility in immune response. Thus, cucurbitacin is a promising class of anticancer agents that can be used alone or in combination with chemotherapy and radiotherapy for the treatment of many types of cancer.Therefore, based on the research reports in the past five years at home and abroad, we further summarize and review the structural characteristics, chemical and biological activities, and studies of cucurbitacins based on the previous studies to provide a reference for further development and utilization of cucurbitacins.

Cucurbitacins as potential anticancer agents: new insights on molecular mechanisms.

Since ancient times, plants have been an extensive reservoir of bioactive compounds with therapeutic interest for new drug development and clinical application. Cucurbitacins are a compelling example of these drug leads, primarily present in the plant kingdom, especially in the Cucurbitaceae family. However, these natural compounds are also known in several genera within other plant families. Beyond the Cucurbitaceae family, they are also present in other plant families, as well as in some fungi and one shell-less marine mollusc. Despite the natural abundance of cucurbitacins in different natural species, their obtaining and isolation is limited, as a result, an increase in their chemical synthesis has been developed by researchers. Data on cucurbitacins and their anticancer activities were collected from databases such as PubMed/MedLine, TRIP database, Web of Science, Google Scholar, and ScienceDirect and the information was arranged sequentially for a better understanding of the antitumor potential. The results of the studies showed that cucurbitacins have significant biological activities, such as anti-inflammatory, antioxidant, antimalarial, antimicrobial, hepatoprotective and antitumor potential. In conclusion, there are several studies, both in vitro and in vivo reporting this important anticancer/chemopreventive potential; hence a comprehensive review on this topic is recommended for future clinical research.

Cucurbitacins and the Immune System: Update in Research on Anti- inflammatory, Antioxidant, and Immunomodulatory Mechanisms.

Cucurbitacins are a wide group of natural products found in several plant families, especially in the Cucurbitaceae family. In the last decade, there has been a significant increase in studies aimed at identifying new biological activities of cucurbitacins and describing their mechanisms of action. The most researched pharmacological activities are antineoplastic and anti-inflammatory activity, the first being recently reviewed. The present review explains the anti-inflammatory, antioxidant, and immunomodulatory potential of cucurbitacins, identifying the most studied compounds in this area and exploring their mechanisms of action already studied. A brief report was made about the main structural characteristics of cucurbitacins, in addition to an update on the biological activities attributed to this class in the last 5 years. Cucurbitacin B and cucurbitacin E have been identified as the most investigated when it comes to the immune response, playing roles in both innate and adaptive immunity. The most cited mechanisms were inhibition of COX-2 and NOS, reduction of oxidative stress, suppression of proinflammatory cytokines and modulation of acquired immunity proteins. It was found that cucurbitacins are promising molecules in the search for therapeutic innovation and have wide versatility in the immune response.

Luffa operculata at a late period of gestation dysregulates melatonin and cytokines interfering with weight of dams and their male offspring.

ETHNOPHARMACOLOGICAL RELEVANCE: The tea made with the fruits of Luffa operculata (L.) Cogn. (Cucurbitaceae; EBN) is popularly used as abortive. AIM OF THE STUDY: The present work aimed at accessing how the exposition of female Wistar rats to 1.0 mg/kg of EBN (experimental group, EG), or distilled water (control group, CG), by gavage, at gestational days (GD) 17-21 interfered with the reproductive performance, and with dams' behavior after weaning. MATERIALS AND METHODS: At post-natal day 2 (PND2), the number of male and female pups was evaluated, as well as their weight. After weaning (PND21), dams were euthanized, and their liver and kidneys were removed for histological and biochemical analyses, while the blood was used in the evaluation of cytokines IL-1α, IL-1ß, IL-6 and TNF-α, corticosterone, adrenocorticotrophic hormone, melatonin, AST, ALT and creatinine levels. RESULTS AND DISCUSSION: Dams that were treated with EBN showed an anxiety-like behavior, weight loss at the end of gestation and weight gain at weaning, accompanied with a significant decrease in pro-inflammatory cytokines and in the melatonin level. No significant histological or biochemical alterations have occurred in the liver or kidneys. The number of female pups was significantly higher in the EG. The male pups showed weight gain at PND60. CONCLUSION: The presence of cucurbitacins is probably involved in the dysregulations that were found, due to their polycyclic steroid triterpene structure.

Synthesis and biological studies of c(RGDyK) conjugates of cucurbitacins.

Cucurbitacins (CUCUs) are triterpenoids known to display potent cytotoxic effects; however, their clinical application is limited due to poor pharmacokinetics and systemic toxicity. This work focuses on the development of c(RGDyK)-CUCU conjugates for the selective delivery of CUCUs to integrin-overexpressing cancer cells. The activity of the conjugates against various cancer cells was studied. They exhibited a mild cytostatic effect to six cancer cell lines and a cytotoxic effect against integrin-overexpressing MCF-7 and A549 cells. Their chemical and metabolic stability was extensively studied using LC-MS analysis. The conjugates maintained high affinity for αvß3 integrin receptors. c(RGDyK) conjugation via a PEG linker was beneficial for CUCU-D and the resulting conjugate was approximately three-times more active than the free CUCU-D in MCF7 cells.

Cucurbitacin IIa: A review of phytochemistry and pharmacology.

Cucurbitacin IIa was first found in plants and it belongs to tetracyclo triterpenoids. It is one of the most important active components in cucurbitaceae plants. Studies have found that cucurbitacin IIa has a variety of pharmacological effects, such as antitumor, antiinflammatory, antibacterial, antihepatitis B virus, inhibition of human immunodeficiency virus replication, and antidepressant effect. However, the underlying mechanisms, intracellular targets, and structure-activity relationships of cucurbitacin IIa remain to be completely elucidated. This review summarizes the current advances concerning the phytochemistry and pharmacology of cucurbitacin IIa. Electronic databases such as PubMed, Web of Science, Google Scholar, Science Direct, and CNKI were used to find relevant information about cucurbitacin IIa using keywords such as "Cucurbitacin IIa," "Pharmacology," and "Phytochemistry." These pharmacological effects involve the actin cytoskeleton aggregation, the regulation of JAK2/STAT3, ERBB-MAPK, CaMKII α/CREB/BDNF signal pathways, as well as the regulation of survivin, caspases, and other cell cycles, apoptosis, autophagy-related cytokines, and kinases. It has high development and use value.

Suppressive Effect of Two Cucurbitane-Type Triterpenoids from Momordica charantia on Cutibacterium acnes-Induced Inflammatory Responses in Human THP-1 Monocytic Cell and Mouse Models.

Cutibacterium acnes (formerly Propionibacterium acnes) is one of the major bacterial species responsible for acne vulgaris. Numerous bioactive compounds from Momordica charantia Linn. var. abbreviata Ser. have been isolated and examined for many years. In this study, we evaluated the suppressive effect of two cucurbitane-type triterpenoids, 5ß,19-epoxycucurbita-6,23-dien-3ß,19,25-triol (Kuguacin R; KR) and 3ß,7ß,25-trihydroxycucurbita-5,23-dien-19-al (TCD) on live C. acnes-stimulated in vitro and in vivo inflammatory responses. Using human THP-1 monocytes, KR or TCD suppressed C. acnes-induced production of interleukin (IL)-1ß, IL-6 and IL-8 at least above 56% or 45%, as well as gene expression of these three pro-inflammatory cytokines. However, a significantly strong inhibitory effect on production and expression of tumor necrosis factor (TNF)-α was not observed. Both cucurbitanes inhibited C. acnes-induced activation of the myeloid differentiation primary response 88 (MyD88) (up to 62%) and mitogen-activated protein kinases (MAPK) (at least 36%). Furthermore, TCD suppressed the expression of pro-caspase-1 and cleaved caspase-1 (p10). In a separate study, KR or TCD decreased C. acnes-stimulated mouse ear edema by ear thickness (20% or 14%), and reduced IL-1ß-expressing leukocytes and neutrophils in mouse ears. We demonstrated that KR and TCD are potential anti-inflammatory agents for modulating C. acnes-induced inflammation in vitro and in vivo.

Lipid-Lowering Activities of Cucurbitacins Isolated from Trichosanthes cucumeroides and Their Synthetic Derivatives.

In the ongoing efforts to discover natural cholesterol-lowering compounds, dihydrocucurbitacin B, isolated from Trichosanthes cucumeroides roots, was found to promote LDL uptake by upregulating LDLR protein in a PCSK9-dependent process. In this study, an in-depth investigation of T. cucumeroides roots afforded 27 cucurbitacins (1-27), including seven new cucurbitacins (1-7), and their structures were elucidated by spectroscopic data analyses. In order to gain insight into their structure-activity relationship, cucurbitacin derivatives (B1-11 and DB1-11) were synthesized. Evaluation of lipid-lowering activities of these cucurbitacins by an LDL uptake assay in HepG2 cells revealed that most of the compounds improved the LDL uptake rate, among which hexanorisocucurbitacin D (6) and isocucurbitacin D (21) exhibited the highest activities (rates of 2.53 and 2.47, respectively), which were comparable to that of the positive control, nagilactone B (rate of 2.07). According to a mechanistic study by Western blot analysis, compounds 6 and 21 dose-dependently increased LDLR protein levels and reduced PCSK9 protein levels, representing promising new lipid-lowering drug candidates.

Critical enzymes for biosynthesis of cucurbitacin derivatives in watermelon and their biological significance.

Various cucurbitacins have been isolated, and their structures have been elucidated. Owing to their economic potential and importance as active pharmacological compounds, their cytotoxicity in various cancer cells has been assessed. Here, we mined several candidate genes with potential involvement in cucurbitacin biosynthesis in watermelon (Citrullus lanatus) and performed in vitro enzymatic assays and instrumental analyses using various substrates to identify cucurbitacin functions and products. Enzymatic activities of two acetyltransferases (ACTs) and one UDP-glucosyltransferase (UGT) against cucurbitacins were confirmed, resulting in the synthesis of novel cucurbitacins in vivo and/or in vitro to our knowledge. As ACTs and UGT are involved in the dynamic conversion of cucurbitacins by catalyzing acetylation and glucosylation at moieties in the cucurbitacins skeleton, these findings improve our knowledge on how these genes contribute to the diversity of cucurbitacins.

Cucurbitacin IIb from Ibervillea sonorae Induces Apoptosis and Cell Cycle Arrest via STAT3 Inhibition.

BACKGROUND: Cucurbitacin IIb (CIIb) from Ibervillea sonorae has a high capacity to suppress cancer cell proliferation and induce apoptosis. This study investigated the molecular mechanisms related to the antiproliferative and apoptosis induction capacity of CIIb in HeLa cells. MATERIALS AND METHODS: The cell viability and anti-proliferative effect of CIIb were evaluated by using the trypan blue exclusion assay. The effect of CIIb on the mitochondrial membrane potential was determined by flow cytometry using JC-1. The activity of caspase-3 and caspase-9 was evaluated by flow cytometry using commercial kits. The effect of CIIb on the cell cycle was investigated using Fluorescence-Activated Cell Sorting (FACS) analysis. Western blot analysis was used to evaluate both the inhibitory effect of CIIb on the STAT3 signaling pathway and cyclin -B1, and DNA damage by the comet assay. RESULTS: CIIb triggers disruption of the mitochondrial membrane potential (Δψm) and consequently activated the caspases -3 and -9, as a result of the activation of the intrinsic pathway of the apoptosis. Likewise, the CIIbinduced cell cycle was arrested in S and G2/M after 24h of treatment. CIIb also reduced the expression of STAT3 and cyclin -B1. Finally, CIIb produced an antiproliferative effect at 48 and 72 h, inducing DNA damage. CONCLUSION: These results demonstrate CIIb-induced apoptosis and cell cycle arrest in HeLa through the inhibition of STAT3.

Nor-cucurbitacins from the leaves of Mareya micrantha (Benth.) Müll. Arg. (Euphorbiaceae).

Mareya micrantha, an Ivoirian medicinal plant, was investigated for its chemical constituents and antioxidant properties. This study carried out on the hydroethanolic extract of the leaves led to three new nor-cucurbitacins named: 29-nor-1,2,3,4,5,10-dehydro-3,15α,20ß-trihydroxy-16α-acetyl-11,22-dioxo-cucurbita-23-ene 2-O-ß-D-glucopyranoside (1), 29-nor-2ß,20ß,25-trihydroxy-16α-acetyl-3,11,22-trioxo-cucurbita-4,23-diene (2) and 29-nor-2ß,15α,20ß-trihydroxy-16α-acetyl-3,11,22-trioxo-cucurbita-4,23-diene 2-O-ß-D-glucopyranoside (3). The structures were established on the basis of spectral data (NMR, UV, MS and IR). The antioxidant properties evaluated by DPPH and CUPRAC methods gave the best activity with compound 1. The chemotaxonomic significance of the isolation of these compounds in Mareya micrantha, a species belonging to the Euphorbiaceae family, is discussed.

Cucurbitacin IIb, a steroidal triterpene from Ibervillea sonorae induces antiproliferative and apoptotic effects on cervical and lung cancer cells.

Chemical studies on Ibervillea sonorae (S. Watson) Greene root led to isolation and chemical characterization of diverse cucurbitacin triterpenoid compounds such as kinoin A, B, C, and their glucosides. In previous studies, we demonstrated that kinoin A inhibits the cell proliferation on diverse cell line and induce apoptosis in HeLa cells. Therefore, the study of the isolated compounds from the extracts continued to be necessary. The objective of the present work was to isolate and chemically characterize the active compounds of the methanolic extract of the roots of I. sonorae and to evaluate their antiproliferative activity and induction of apoptosis. By chromatographic column separation and using NMR spectroscopy experiments, cucurbitacin IIb (CIIb), known as 23,24-dihydrocucurbitacin F or hemslecin B, was isolated and identified for the first time as a chemical constituent of the crude methanolic extract of this plant. The antiproliferative activity of CIIb was evaluated by MTT assay, and the apoptosis induction capacity was monitored by annexin V-FITC/propidium iodide using flow cytometry. CIIb showed a pronounced effect on the proliferation of HeLa and A549 tumor cells, with IC50 of 7.3 and 7.8 µM, respectively, but was less effective against L929 non-cancerous murine cell line. Apoptosis induction capacity of CIIb on HeLa and A549 was monitored by annexin V-FITC/propidium iodide using flow cytometry. Exposure of HeLa and A549 with CIIb (8 µM) for 24 h increased 56.9 and 52.3% respectively of the total apoptosis compared to the negative control (p < 0.005). CIIb, isolated for the first time from I. sonorae, showed antiproliferative activity against HeLa and A549 cell lines by inducing cell death by apoptosis.

Metabolite Profiling and Quantitation of Cucurbitacins in Cucurbitaceae Plants by Liquid Chromatography coupled to Tandem Mass Spectrometry.

Cucurbitaceae is an important plant family because many of its species are consumed as food, and used in herbal medicines, cosmetics, etc. It comprises annual vines and is rich in various bioactive principles which include the cucurbitacins. These steroidal natural products, derived from the triterpene cucurbitane, are mainly the bitter principles of the family Cucurbitaceae. Their biological activities include anti-inflammatory, hepatoprotective, and anti-cancer activities. A total of 10 species belonging to 6 genera of the Cucurbitaceae family along with Cissampelos pareira (Menispermaceae) were included in this study. A comprehensive profiling of certain natural products was developed using HPLC-QTOF-MS/MS analysis and a distribution profile of several major natural products in this family was obtained. A total of 51 natural products were detected in both positive and negative ionization modes, based on accurate masses and fragmentation patterns. Along with this, quantitation of four bioactive cucurbitacins, found in various important plants of the Cucurbitaceae family, was carried out using multiple reaction monitoring (MRM) approach on an ion trap mass spectrometer. Cucurbitacin Q was found to be the most abundant in C. pareira, while Citrullus colocynthis contained all four cucurbitacins in abundant quantities. The developed quantitation method is simple, rapid, and reproducible.

Identification and characterization of the Cucurbitacins, a novel class of small-molecule inhibitors of Tropomyosin receptor kinase a.

BACKGROUND: NGF-TrkA is well known to play a key role in propagating and sustaining pruritogenic signals, which form the pathology of chronic pruritus. Inhibition of NGF-TrkA is a known strategy for the treatment of pruritus. In the present paper, we describe the identification, in vitro characterization, structure-activity analysis, and inhibitory evaluation of a novel TrkA inhibitory scaffold exemplified by Cucurbitacins (Cus). METHODS: Cus were identified as TrkA inhibitors in a large-scale kinase library screen. To obtain structural models of Cus as TrkA inhibitors, AutoDock was used to explore their binding to TrkA. Furthermore, PC12 cell culture systems have been used to study the effects of Cus and traditional Chinese medicinal plants (Tian Gua Di and bitter gourd leaf) extracts on the kinase activity of TrkA. RESULTS: Cus block the phosphorylation of TrkA on several tyrosine sites, including Tyr490, Tyr674/675, and Tyr785, and inhibit downstream Akt and MAPK phosphorylation in response to NGF in PC12 cell model systems. Furthermore, traditional Chinese medicinal plants (Tian Gua Di and bitter gourd leaf) containing Cu extracts were shown to inhibit the phosphorylation of TrkA and Akt. These data reveal mechanisms, at least partly, of the anti-pruritus bioactivity of Cus. CONCLUSION: Taken together, with the recent discovery of the important role of TrkA as a therapeutic target, Cus could be the basis for the design of improved TrkA kinase inhibitors, which could someday help treat pruritus.

Cucurbitacin IIa interferes with EGFR-MAPK signaling pathway leads to proliferation inhibition in A549 cells.

Cucurbitacin IIa (CuIIa), a tetracyclic triterpenoid harboring anticancer activity, was investigated in A549 cells to reveal its mechanism of targeting on epidermal growth factor receptor (EGFR) signaling pathway. Results showed that CuIIa was capable of inducing apoptosis and cell cycle arrest at G2/M phase. The transcription of EGFR pathway genes and their proteins accumulation was inconsistently influenced by CuIIa. Notably, transcription of Raf1 was significantly upregulated, nevertheless, MEK1 and ERK1 were significantly downregulated. On the other hand, the accumulation of the total and phosphorylated proteins of the most members in EGFR-mitogen-activated protein kinase (MAPK) pathway, as well as CylclinB1 and survivin were also shifted by CuIIa treatment. Remarkably, total MEK remained constant but survivin completely degraded. Moreover, phosphorylated BRAF continuously increased while Raf1 and MEK decreased continuously. CuIIa was further confirmed to be a tyrosine kinase inhibitor (TKI) of EGFR by kinase inhibition assay. The results of molecular simulation showed that the long side chain of CuIIa occupied the binding pocket of EGFR and the ligand was stabilized at the active site of EGFR. In view of the results above, it is suggested that CuIIa inhibits cell proliferation by interfering the EGFR-MAPK signaling pathway.

Cucurbits Plants: A Key Emphasis to Its Pharmacological Potential.

Cucurbita genus has received a renowned interest in the last years. This plant species, native to the Americas, has served worldwide folk medicine for treating gastrointestinal diseases and intestinal parasites, among other clinical conditions. These pharmacological effects have been increasingly correlated with their nutritional and phytochemical composition. Among those chemical constituents, carotenoids, tocopherols, phenols, terpenoids, saponins, sterols, fatty acids, and functional carbohydrates and polysaccharides are those occurring in higher abundance. However, more recently, a huge interest in a class of triterpenoids, cucurbitacins, has been stated, given its renowned biological attributes. In this sense, the present review aims to provide a detailed overview to the folk medicinal uses of Cucurbita plants, and even an in-depth insight on the latest advances with regards to its antimicrobial, antioxidant and anticancer effects. A special emphasis was also given to its clinical effectiveness in humans, specifically in blood glucose levels control in diabetic patients and pharmacotherapeutic effects in low urinary tract diseases.

Cucurbitacins inspired organic synthesis: Potential dual inhibitors targeting EGFR - MAPK pathway.

Natural products have been known as a fundamental source for drug discovery leading to the evolution of Biological Oriented Organic Synthesis (BIOS) approach to assemble natural product mimics. Herein, a series of Cucurbitacin inspired estrone analogs was assembled to generate 18 novel synthesized analogs via installation of double bond across C-16/C-17 positions of estrone scaffold and diastereomeric separation of (R) and (S) at C-20. This was followed by biological screening against HEPG-2 cell lines to exhibit anti-proliferative activity ranging from IC50 0.70-32 µM. Two analogs (MMA-102 and MMA-132) were chosen for further biological elucidation to exhibit dual inhibitory mechanism against the phosphorylating pathways of EGFR and MAPK (RAS/RAF/MEK/ERK) pathways. Both of MMA-102 and MMA-132 showed cell cycle arrest with elevated levels of apoptotic parameters. Molecular modeling simulations suggested the potential of MMA-102 and MMA-132 to compete with ATP within the catalytic binding domains of EGFR and MAPK pathway.

Design, synthesis and biological study of hybrid drug candidates of nitric oxide releasing cucurbitacin-inspired estrone analogs for treatment of hepatocellular carcinoma.

Development of hybrid drug candidates is well known strategy for designing antitumor agents. Herein, a novel class of nitric oxide donating cucurbitacin inspired estrone analogs (NO-CIEAs) were designed and synthesized as multitarget agents. Synthesized analogs were initially evaluated for their anti-hepatocellular carcinoma activities. Among the tested analogs, NO-CIEAs 17 and 20a exhibited more potent activity against HepG2 cells (IC50 = 4.69 and 12.5 µM, respectively) than the reference drug Erlotinib (IC50 = 25 µM). Interestingly, NO-CIEA 17 exerted also a high potent activity against Erlotinib-resistant HepG2 cell line (HepG2-R) (IC50 = 8.21 µM) giving insight about its importance in drug resistance therapy. Intracellular measurements of NO revealed that NO-CIEAs 17 and 20a showed a significant increase in NO production in tumor cells after 1 h of incubation comparable to the reference prodrug JS-K. Flow cytometric analysis showed that both NO-CIEAs 17 and 20a mainly arrested the HepG2 cells in the G0/G1 phase. Also, In-Cell Based ELISA screening showed that NO-CIEA 17 resulted in a potential inhibitory activity towards the EGFR and MAPK (25% and 29% inhibition compared to untreated control cells, respectively). This data suggests the binding ability of NO-CIEA 17 to the EGFR and ERK to be well correlated along with the docking and cellular studies. Also, treatment of HepG2-R cells with NO-CIEA 17 showed a potential reduction of MRP2 expression in a dose dependent manner providing a significant impact on the chemotherapeutic resistance. Overall, the current study provides a potential new approach for the discovery of a novel antitumor agent against HCC.

Cucurbitacins as Anticancer Agents: A Patent Review.

BACKGROUND: Cucurbitacins belong to a group of tetracyclic triterpenoids that display a wide range of biological effects. In the past, numerous cucurbitacins have been isolated from natural sources and many active compounds have been synthesized using the privileged scaffold in order to enhance its cytotoxic effects. OBJECTIVE: This review covers patents on the therapeutic effects of natural cucurbitacins and their synthetic analogs published during the past decade. By far, the majority of patents published are related to cancer and Structure-Activity Relationships (SAR) of these compounds are included to lend gravitas to this important class of natural products. METHODS: The date about the published patents was downloaded via online open access patent databases. RESULTS: Cucurbitacins display significant cytotoxic properties, in particular cucurbitacins B and D which possess very potent effects towards a number of cancer cells. Numerous cucurbitacins isolated from natural sources have been derivatized through chemical modification at the C(2)-OH and C(25)- OH groups. Most importantly, an acyl ester of the C(25)-OH and, iso-propyl, n-propyl and ethyl ether groups of the C(2)-OH demonstrated the most increased cytotoxic activity. CONCLUSION: The significant cytotoxic effects of natural and semi-synthetic cucurbitacins make them attractive as new drug candidates. Moreover, cucurbitacins have the capability to form conjugates with other anticancer drugs which will synergistically enhance their anticancer effects. The authors believe that in order to get lead compounds, there should be a greater focus on the synthesis of homodimers, heterodimers, and halo derivatives of cucurbitacins. In the opinion of the authors the analysis of the published patents on the cucurbitacins indicates that these compounds can be developed into a regimen to treat a wide spectrum of cancers.

Isolation of anticancer constituents from Cucumis prophetarum var. prophetarum through bioassay-guided fractionation.

BACKGROUND: Cucumis prophetarum var. prophetarum is used in Saudi folk medicine for treating liver disorders and grows widely between Abha and Khamis Mushait City, Saudi Arabia. METHODS: Bioassay-guided fractionation and purification were used to isolate the main active constituents of Cucumis prophetarum var. prophetarum fruits. These compounds were structurally elucidated using NMR spectroscopy, mass spectral analyses and x-ray crystallography. All fractions, sub-fractions and pure compounds were screened for their anticancer activity against six cancer cell lines. RESULTS: The greatest cytotoxic activity was found to be in the ethyl acetate fraction, resulting in the isolation of five cucurbitacin compounds [E, B, D, F-25 acetate and Hexanorcucurbitacin D]. Among the cucurbitacins that were isolated and tested cucurbitacin B and E showed potent cytotoxicity activities against all six human cancer cell lines. CONCLUSION: Human breast cancer cell lines were found to be the most sensitive to cucurbitacins. Preliminary structure activity relationship (SAR) for cytotoxic activity of Cucurbitacins against human breast cancer cell line MDA-MB-231 has been reported.