Diterpenes Isolated from Three Different Plectranthus Sensu Lato Species and Their Antiproliferative Activities against Gynecological and Glioblastoma Cancer Cells.

Fourteen diterpenes were isolated from methanol extracts of the aerial parts ofColeus comosus,Coleus forsteri "Marginatus", and Plectranthus ciliatus. The compounds belong to the abietane (1-4, 9-11, and 13), ent-clerodane (5-8), and ent-kaurane (14, 15) classes. Three new compounds were isolated from C. comosus, including 3-O-acetylornatin G (2), 3,12-di-O-acetylornatin G (3), ornatin B methyl ester (5), and ornatin F (4), for which we proposed a revised structure. The structures of the compounds were determined by comprehensive spectroscopic data analysis. The isolated diterpenes were examined in silico for their physicochemical and early ADME properties. Their antiproliferative effects were determined in vitro using human breast (MDA-MB-231 and MCF-7), cervical (HeLa), and glioblastoma (U-87 MG) cancer cell lines. The royleanone- and hydroquinone-type abietane diterpenes (9-13)exhibited the most potent antiproliferative activity against all cancer cell lines tested, particularly against glioblastoma cells, with IC50 values ranging from 1.1 to 15.6 µM.

Synthesis of Estrone Heterodimers and Evaluation of Their In Vitro Antiproliferative Activity.

Directed structural modifications of natural products offer excellent opportunities to develop selectively acting drug candidates. Natural product hybrids represent a particular compound group. The components of hybrids constructed from different molecular entities may result in synergic action with diminished side effects. Steroidal homo- or heterodimers deserve special attention owing to their potentially high anticancer effect. Inspired by our recently described antiproliferative core-modified estrone derivatives, here, we combined them into heterodimers via Cu(I)-catalyzed azide-alkyne cycloaddition reactions. The two trans-16-azido-3-(O-benzyl)-17-hydroxy-13α-estrone derivatives were reacted with 3-O-propargyl-D-secoestrone alcohol or oxime. The antiproliferative activities of the four newly synthesized dimers were evaluated against a panel of human adherent gynecological cancer cell lines (cervical: Hela, SiHa, C33A; breast: MCF-7, T47D, MDA-MB-231, MDA-MB-361; ovarian: A2780). One heterodimer (12) exerted substantial antiproliferative activity against all investigated cell lines in the submicromolar or low micromolar range. A pronounced proapoptotic effect was observed by fluorescent double staining and flow cytometry on three cervical cell lines. Additionally, cell cycle blockade in the G2/M phase was detected, which might be a consequence of the effect of the dimer on tubulin polymerization. Computational calculations on the taxoid binding site of tubulin revealed potential binding of both steroidal building blocks, mainly with hydrophobic interactions and water bridges.

Herbal compounds as promising therapeutic agents in precision medicine strategies for cancer: A systematic review.

BACKGROUND: The field of personalized medicine has gained increasing attention in cancer care, with the aim of tailoring treatment strategies to individual patients for improved outcomes. Herbal medicine, with its long-standing historical use and extensive bioactive compounds, offers a rich source of potential treatments for various diseases, including cancer. OBJECTIVE: To provide an overview of the current knowledge and evidence associated with incorporating herbal compounds into precision medicine strategies for cancer diseases. Additionally, to explore the general characteristics of the studies included in the analysis, focusing on their key features and trends. SEARCH STRATEGY: A comprehensive literature search was conducted from multiple online databases, including PubMed, Scopus, Web of Science, and CINAHL-EBSCO. The search strategy was designed to identify studies related to personalized cancer medicine and herbal interventions. INCLUSION CRITERIA: Publications pertaining to cancer research conducted through in vitro, in vivo, and clinical studies, employing natural products were included in this review. DATA EXTRACTION AND ANALYSIS: Two review authors independently applied inclusion and inclusion criteria, data extraction, and assessments of methodological quality. The quality assessment and biases of the studies were evaluated based on modified Jadad scales. A detailed quantitative summary of the included studies is presented, providing a comprehensive description of their key features and findings. RESULTS: A total of 121 studies were included in this review for analysis. Some of them were considered as comprehensive experimental investigations both in vitro and in vivo. The majority (n = 85) of the studies included in this review were conducted in vitro, with 44 of them specifically investigating the effects of herbal medicine on animal models. Additionally, 7 articles with a combined sample size of 31,271 patients, examined the impact of herbal medicine in clinical settings. CONCLUSION: Personalized medication can optimize the use of herbal medicine in cancer treatment by considering individual patient factors such as genetics, medical history, and other treatments. Additionally, active phytochemicals found in herbs have shown potential for inhibiting cancer cell growth and inducing apoptosis, making them a promising area of research in preclinical and clinical investigations. Please cite this article as: Tayeb BA, Kusuma IY, Osman AAM, Minorics R. Herbal compounds as promising therapeutic agents in precision medicine strategies for cancer: A systematic review. J Integr Med. 2024; 22(2): 137-162.

Thymoquinone-protoflavone hybrid molecules as potential antitumor agents.

We describe herein the synthesis of eight new ester-coupled hybrid compounds from thymoquinone and protoflavone building blocks, and their bioactivity testing against multiple cancer cell lines. Among the hybrids, compound 14 showed promising activities in all cell lines studied. The highest activities were recorded against breast cancer cell lines with higher selectivity to MDA-MB-231 as compared to MCF-7. Even though the hybrids were found to be completely hydrolysed in 24 h under cell culture conditions, compound 14 demonstrated a ca. three times stronger activity against U-87 glioblastoma cells than a 1:1 mixture of its fragments. Further, compound 14 showed good tumour selectivity: it acted 4.4-times stronger on U-87 cells than on MRC-5 fibroblasts. This selectivity was much lower, only ca. 1.3-times, when the cells were co-treated with a 1:1 mixture of its non-coupled fragments. Protoflavone-thymoquinone hybrids may therefore serve as potential new antitumor leads particularly against glioblastoma.

Mannich-type modifications of (-)-cannabidiol and (-)-cannabigerol leading to new, bioactive derivatives.

(-)-Cannabidiol (CBD) and (-)-cannabigerol (CBG) are two major non-psychotropic phytocannabinoids that have many beneficial biological properties. However, due to their low water solubility and prominent first-pass metabolism, their oral bioavailability is moderate, which is unfavorable for medicinal use. Therefore, there is a great need for appropriate chemical modifications to improve their physicochemical and biological properties. In this study, Mannich-type reaction was used for the synthetic modification of CBD and CBG for the first time, and thus fifteen new cannabinoid derivatives containing one or two tertiary amino groups were prepared. Thereafter the antiviral, antiproliferative and antibacterial properties of the derivatives and their effects on certain skin cells were investigated. Some modified CBD derivatives showed remarkable antiviral activity against SARS-CoV-2 without cytotoxic effect, while synthetic modifications on CBG resulted in a significant increase in antiproliferative activity in some cases compared to the parent compound.

Antiproliferative and Antimetastatic Properties of 16-Azidomethyl Substituted 3-O-Benzyl Estrone Analogs.

Four diastereomers of 16-azidomethyl substituted 3-O-benzyl estradiol (1-4) and their two estrone analogs (16AABE and 16BABE) were tested for their antiproliferative properties against human gynecological cancer cell lines. The estrones were selected for additional experiments based on their outstanding cell growth-inhibiting activities. Both compounds increased hypodiploid populations of breast cancer cells, and 16AABE elicited cell cycle disturbance as evidenced by flow cytometry. The two analogs substantially increased the rate of tubulin polymerization in vitro. 16AABE and 16BABE inhibited breast cancer cells' migration and invasive ability, as evidenced by wound healing and Boyden chamber assays. Since both estrone analogs exerted remarkable estrogenic activities, as documented by a luciferase reporter gene assay, they can be considered as promising drug candidates for hormone-independent malignancies.

Investigation of Anticancer Properties of Monoterpene-Aminopyrimidine Hybrids on A2780 Ovarian Cancer Cells.

The present study aimed to characterize the antiproliferative and antimetastatic properties of two recently synthesized monoterpene-aminopyrimidine hybrids (1 and 2) on A2780 ovary cancer cells. Both agents exerted a more pronounced cell growth inhibitory action than the reference agent cisplatin, as determined by the MTT assay. Tumor selectivity was assessed using non-cancerous fibroblast cells. Hybrids 1 and 2 induced changes in cell morphology and membrane integrity in A2780 cells, as evidenced by Hoechst 33258-propidium iodide fluorescent staining. Cell cycle analysis by flow cytometry revealed substantial changes in the distribution of A2780 ovarian cancer cells, with an increased rate in the subG1 and G2/M phases, at the expense of the G1 cell population. Moreover, the tested molecules accelerated tubulin polymerization in a cell-free in vitro system. The antimetastatic properties of both tested compounds were investigated by wound healing and Boyden chamber assays after 24 and 48 h of incubation. Treatment with 1 and 2 resulted in time- and concentration-dependent inhibition of migration and invasion of A2780 cancer cells. These results support that the tested agents may be worth of further investigation as promising anticancer drug candidates.

Investigation of the Antineoplastic Effects of 2-(4-Chlorophenyl)-13α-Estrone Sulfamate against the HPV16-Positive Human Invasive Cervical Carcinoma Cell Line SiHa.

Cervical carcinoma is one of the most frequent malignant gynecological cancers in women of reproductive age. Because of the poor tolerability of currently available chemotherapeutic agents, efforts have been focused on developing innovative molecules, including steroids, that exert antineoplastic effects with a better safety profile. In addition to their endocrine properties, certain estrogens exhibit additional biological activities, such as antiangiogenic and anticancer effects. Based on previous studies, the antineoplastic properties of 13α-estrone sulfamate derivatives (13AES1-3) were investigated, and the mechanism of action for the most promising compound 13AES3 was explored. Based on their effects on the viability of different human adherent gynecological cancer cells, the SiHa cervical cell line was used for mechanistic experiments. The most active analog 13AES3 was shown to exert considerable proapoptotic effects, as evidenced by a colorimetric caspase-3 assay and fluorescent double staining. It also elicited antimigratory and anti-invasive effects in a concentration-dependent manner, as evidenced by wound healing and Boyden chamber assays, respectively. Regarding their mechanism of action, 13AES derivatives were shown to inhibit tubulin polymerization, and computer simulations provided a possible explanation for the importance of the presence of the chlorophenyl ring on the estrane skeleton. 13AES3 is considered to be the first 13α-estrone derivative with a significant antineoplastic potency against SiHa cancer cells. Therefore, it might serve as a valuable lead molecule for the design of anticancer agents targeting cervical carcinomas.

Synthesis and Antiproliferative Activity of Steroidal Diaryl Ethers.

Novel 13α-estrone derivatives have been synthesized via direct arylation of the phenolic hydroxy function. Chan-Lam couplings of arylboronic acids with 13α-estrone as a nucleophilic partner were carried out under copper catalysis. The antiproliferative activities of the newly synthesized diaryl ethers against a panel of human cancer cell lines (A2780, MCF-7, MDA-MB 231, HeLa, SiHa) were investigated by means of MTT assays. The quinoline derivative displayed substantial antiproliferative activity against MCF-7 and HeLa cell lines with low micromolar IC50 values. Disturbance of tubulin polymerization has been confirmed by microplate-based photometric assay. Computational calculations reveal significant interactions of the quinoline derivative with the taxoid binding site of tubulin.

Antiproliferative Activity of (-)-Isopulegol-based 1,3-Oxazine, 1,3-Thiazine and 2,4-Diaminopyrimidine Derivatives.

A series of novel heterocyclic structures, namely 1,3-oxazines, 1,3-thiazines and 2,4-diaminopyrimidines, were designed and synthesised. The bioassay tests demonstrated that, among these analogues, 2,4-diaminopyridine derivatives showed significant antiproliferative activity against different human cancer cell lines (A2780, SiHa, HeLa, MCF-7 and MDA-MB-231). Pyrimidines substituted with N2 -(p-trifluoromethyl)aniline, in particular, displayed a potent inhibitory effect on the growth of cancer cells. Structure-activity relationships were also studied from the aspects of stereochemistry on the aminodiol moiety as well as exploring the effects of substituents on the pyrimidine scaffold.

Regioselective synthesis, physicochemical properties and anticancer activity of 2-aminomethylated estrone derivatives.

The unique estrogen receptor (ER)-independent antiproliferative and apoptotic activity of 2-methoxyestradiol (2ME2) is well known, however, its use has been limited because of its poor oral bioavailability. In this study, novel 2-aminomethylated estrone (E) and estradiol (E2) derivatives structurally related to 2ME2 were synthesized, and their physicochemical properties as well as their in vitro cytotoxic effects were investigated in the hope of finding more selective antiproliferative agents with improved pharmacokinetic profile. The target compounds were synthesized from 2-dimethylaminomethylated E obtained regioselectively by a three-component Mannich reaction. Quaternization with methyl iodide followed by reacting the ammonium salt with various dialkyl and alicyclic secondary amines afforded the desired products in good yields. The reactions proceeded via a 1,4-nucleophilic addition of the applied secondary amines to the ortho-quinone methide (o-QM) intermediates, generated in situ from the salt by base-promoted ß-elimination. The compound library has been enlarged with structurally similar E2 analogues obtained by stereoselective reduction and with some 17ß-benzylamino derivatives prepared by reductive amination. The potential values of the novel E and E2 derivatives were characterised by means of three different approaches. At the first step compounds were virtually screened using physicochemical parameters. Physicochemical characterization was completed by kinetic solubility and in vitro intestinal-specific permeability measurement. Antiproliferative effects were additionally determined on a panel of malignant and non-cancerous cell lines. The evaluation of the pharmacological profile of the novel E and E2 derivatives was completed with the calculation of lipophilic efficacy (LiPE).

Novel preparation of substituted oxazolines condensed to d-ring of estrane skeleton and characterization of their antiproliferative properties.

A simple and efficient synthesis of novel estrone 16α,17α-oxazoline derivatives substituted at the D ring (compounds 6a-g) is described. The reduction of 16α-azido-3-methoxyestra-1,3,5-trien-17-one (1) in methanol in the presence of CeCl3 under the condition of the Luche reaction produced two epimeric azido alcohol (16α-azido-17α-hydroxy and 16α-azido-17ß-hydroxy) derivatives of estra-1,3,5(10)-triene-3-methyl ether (compounds 2 and 3) in a yield of 90% and 7.6%. The reaction of the sterically unhindered 16α-azido-17α-hydroxy-estra-1,3,5(10)-triene-3-methyl ether (2) with a range of benzaldehydes under the condition of the Schmidt rearrangement yielded d-ring substituted estrone 16α,17α-oxazoline derivatives 6a-g. The in vitro antiproliferative activities of compounds 1, 2, 3, 6a-g were also determined by means of MTT assays on a panel of human cancer cell lines HeLa, SiHa, C-33 A, A2780, MCF-7, MDA-MB-231 and T47D.

Microwave-assisted Phospha-Michael addition reactions in the 13α-oestrone series and in vitro antiproliferative properties.

Microwave-assisted phospha-Michael addition reactions were carried out in the 13α-oestrone series. The exocyclic 16-methylene-17-ketones as α,ß-unsaturated ketones were reacted with secondary phosphine oxides as nucleophilic partners. The addition reactions furnished the two tertiary phosphine oxide diastereomers in high yields. The main product was the 16α-isomer. The antiproliferative activities of the newly synthesised organophosphorus compounds against a panel of nine human cancer cell lines were investigated by means of MTT assays. The most potent compound, the diphenylphosphine oxide derivative in the 3-O-methyl-13α-oestrone series (9), exerted selective cell growth-inhibitory activity against UPCI-SCC-131 and T47D cell lines with low micromolar IC50 values. Moreover, it displayed good tumour selectivity property determined against non-cancerous mouse fibroblast cells.

Synthesis and evaluation of anticancer activities of 2- or 4-substituted 3-(N-benzyltriazolylmethyl)-13α-oestrone derivatives.

2- or 4-Substituted 3-N-benzyltriazolylmethyl-13α-oestrone derivatives were synthesised via bromination of ring A and subsequent microwave-assisted, Pd-catalysed C(sp2)-P couplings. The antiproliferative activities of the newly synthesised brominated and phosphonated compounds against a panel of human cancer cell lines (A2780, MCF-7, MDA-MB 231) were investigated by means of MTT assays. The most potent compound, the 3-N-benzyltriazolylmethyl-4-bromo-13α-oestrone derivative exerted substantial selective cell growth-inhibitory activity against A2780 cell line with a submicromolar IC50 value. Computational calculations reveal strong interactions of the 4-bromo derivative with both colchicine and taxoid binding sites of tubulin. Disturbance of tubulin function has been confirmed by photometric polymerisation assay.

Synthesis of Artemisinin-Estrogen Hybrids Highly Active against HCMV, P. falciparum, and Cervical and Breast Cancer.

Artemisinin-estrogen hybrids were for the first time both synthesized and investigated for their in vitro biological activity against malaria parasites (Plasmodium falciparum 3D7), human cytomegalovirus (HCMV), and a panel of human malignant cells of gynecological origin containing breast (MCF7, MDA-MB-231, MDA-MB-361, T47D) and cervical tumor cell lines (HeLa, SiHa, C33A). In terms of antimalarial efficacy, hybrid 8 (EC50 = 3.8 nM) was about two times more active than its parent compound artesunic acid (7) (EC50 = 8.9 nM) as well as the standard drug chloroquine (EC50 = 9.8 nM) and was, therefore, comparable to the clinically used dihydroartemisinin (6) (EC50 = 2.4 nM). Furthermore, hybrids 9-12 showed a strong antiviral effect with EC50 values in the submicromolar range (0.22-0.38 µM) and thus possess profoundly stronger anti-HCMV activity (approximately factor 25) than the parent compound artesunic acid (7) (EC50 = 5.41 µM). These compounds also exerted a higher in vitro anti-HCMV efficacy than ganciclovir used as the standard of current antiviral treatment. In addition, hybrids 8-12 elicited substantially more pronounced growth inhibiting action on all cancer cell lines than their parent compounds and the reference drug cisplatin. The most potent agent, hybrid 12, exhibited submicromolar EC50 values (0.15-0.93 µM) against breast cancer and C33A cell lines.

Antiproliferative Properties of Newly Synthesized 19-Nortestosterone Analogs Without Substantial Androgenic Activity.

19-Nortestosterone C-17 epimers with prominent antiproliferative properties have been previously described. In our present study, five novel 17α-19-nortestosterones (3-7) were synthesized to increase their beneficial biological activities with no associated undesired hormonal effects. The compounds were screened by a viability assay against a panel of human adherent gynecological cancer cell lines. Three of the tested derivatives (3-5) exhibited a remarkable inhibitory effect on the proliferation of HeLa cells with IC50 values lower than that of our reference agent cisplatin (CIS). These three active agents also displayed considerable cancer selectivity as evidenced by their weaker growth inhibitory effect on non-cancerous fibroblast cells compared to CIS. The most potent newly synthesized 17α-chloro derivative (3) was selected for additional experiments in order to characterize its mechanism of action. Since nandrolone (19-nortestosterone, 1) is a structural analog with selective antiproliferative action on cervical carcinoma cells, it was utilized as a positive control in these studies. A lactate dehydrogenase (LDH) assay demonstrated a moderate cytotoxic effect of the test compounds. Cell cycle disturbance and the elevation of the hypodiploid population elicited by the test agents were detected by flow cytometry following propidium staining. The proapoptotic effects of the tested steroids were confirmed by fluorescent microscopy and a caspase-3 activity assay. Treatment-related caspase-9 activation without a substantial change in caspase-8 activity indicates the induction of the intrinsic apoptotic pathway. The selected agents directly influence the rate of tubulin assembly as evidenced by a polymerization assay. Yeast-based reporter gene assay revealed that the androgenic activity of the novel 19-nortestosterone derivative 3 is by multiple orders of magnitude weaker than that of the reference agent 1. Based on the behavior of the examined compounds it can be concluded that a halogen substitution of the 19-nortestosterone scaffold at the 17α position may produce compounds with unique biological activities. The results of the present study support that structurally modified steroids with negligible hormonal activity are a promising basis for the research and development of novel anticancer agents.

Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds.

Research of steroidal compounds as anticancer agents started almost 50 years ago. During the past decades, several innovative new steroids, like cyproterone, finasteride, estramustin, exemestane and fulvestrant have successfully become a part of routine clinical practice. Meanwhile, a vast amount of new information have accumulated about the functions of the endogenous steroid system (including the characterization of enzymes, receptors, transcription pathways, etc.) and about the role of steroids in carcinogenesis. Therefore, it is regularly required to review the latest published results, focusing on a well-defined part within this research field that has definitely developed into a highly diversified speciality by now. Herein, we make an attempt to summarize the most recent results reported about anticancer agents of estrane backbone, focusing on their mechanisms of action and their structure-activity relationships. Due to the vast number and various accessibilities of scientific publications, neither other reviews nor this one can be considered as absolutely exhaustive. In spite of these restrictive factors, the current review makes a good opportunity to define the recent scientific trends in the field of estradiol-related anticancer agents.

Mechanism of antiproliferative action of a new d-secoestrone-triazole derivative in cervical cancer cells and its effect on cancer cell motility.

Cervical cancer is the fourth most frequently diagnosed tumor and the fourth leading cause of cancer death in females worldwide. Cervical cancer is predominantly related with human papilloma virus (HPV) infection, with the most oncogenic types being HPV-18 and -16. Our previous studies demonstrated that some d-secoestrone derivatives exert pronounced antiproliferative activity. The aim of the current investigation was to characterize the mechanism of action of d-secoestrone-triazole (D-SET) on three cervical cancer cell lines with different pathological backgrounds. The growth-inhibitory effects of D-SET were determined by a standard MTT assay. We have found that D-SET exerts a pronounced growth-inhibitory effect on HPV 18-positive HeLa and HPV-negative C-33 A cells, but it has no substantial inhibitory activity on HPV 16-positive SiHa or on intact fibroblast MRC-5 cell lines. After 24h incubation, cells showed the morphological and biochemical signs of apoptosis determined by fluorescent double staining, flow cytometry and caspase-3 activity assay. Besides the elevation of the ratio of cells in the subG1 phase, flow cytometric analysis revealed a cell cycle arrest at G2/M in both HeLa and C-33 A cell lines. To distinguish the G2/M cell population immunocytochemical flow cytometric analysis was performed on HeLa cells. The results show that D-SET significantly increases the ratio of phosphorylated histone H3, indicating cell accumulation in the M phase. Additionally, D-SET significantly increased the maximum rate of microtube formation measured by an in vitro tubulin polymerization assay. Besides its direct antiproliferative activity, the antimigratory property of D-SET has been investigated. Our results demonstrate that D-SET significantly inhibits the migration and invasion of HeLa cells after 24h incubation. These results suggests that D-SET is a potent antiproliferative agent against HPV 16+ and HPV-negative cervical cancer cell lines, with an efficacious motility-inhibiting activity against HPV 16+ cells. Accordingly D-SET can be regarded as a potential drug candidate with a promising new mechanism of action among the antiproliferative steroids, potentially allowing for the design of novel anticancer agents.

Synthesis and biological evaluation of 13α-estrone derivatives as potential antiproliferative agents.

13α-Estrone derivatives containing various substituents on C-3 and C-17 were synthesized, and evaluated by means of MTT assays for in vitro antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF-7, A2780 and A431). Compounds with N-benzyltriazolylmethoxy moieties on C-3 proved to be more potent than their 3-hydroxy or 3-ether counterparts. Some triazoles exerted substantial cytostatic effects against particular tumor cell lines, with submicromolar IC50 values.