Cytotoxic alkaloids from the twigs and leaves of Cephalotaxus sinensis.

Twelve new Cephalotaxus alkaloids (1-12) and nine known analogues (13-21) were isolated and identified from the twigs and leaves of Cephalotaxus sinensis. The structures of the new compounds (1-12) were elucidated by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis. Cephalosine H (8) is the third example of an alkaloid containing the cephalolancine skeleton. Cephalosines J and K (10 and 11) are the rare natural Δ(2)1-alkene-6-hydroxyl homoerythrina-type alkaloids isolated from the Cephalotaxus genus. The racemization of cephalotaxine-type alkaloids is discussed. Alkaloids 6, 7, 11, 16, 18 and 19 exhibited broad and potent cytotoxicities against five human cancer cell lines, with IC50 values ranging from 0.053 to 10.720 µM, highlighting these compounds as promising leads for the development of new antitumor agents.

Isoquinoline alkaloids from Hylomecon japonica and their potential anti-breast cancer activities.

Four pairs of undescribed enantiomeric isoquinoline alkaloids (6S/R-(N,N-diethylacetamido)yl-dihydrochelerythrine, 6R/S-acetonyl-9-hydroxy-dihydrochelerythrine, 6S/R-acroleinyl-dihydrochelerythrine, 6S/R-acetatemethyl-dihydrochelerythrine), five undescribed isoquinoline alkaloids (6,10-dimethoxydihydrochelerythrine, 6-ethoxy-ethaniminyl-dihydrochelandine, 9-hydroxy-dihydrochelerythrine, 9-methoxy-10-hydroxy-norchelerythrine, chelidoniumine A), together with 13 known isoquinoline alkaloids were isolated from an extract of the roots and rhizomes of Hylomecon japonica. The structures of the undescribed compounds were identified by NMR, HRESIMS, UV, IR, and their absolute configurations were defined via electronic circular dichroism data and optical rotation. All of the isolated compounds were tested for their anti-breast cancer activities in MCF-7 cells. Among them, the undescribed alkaloids 6S/R-acroleinyl-dihydrochelerythrine, 6,10-dimethoxydihydrochelerythrine, 6-ethoxy-ethaniminyl-dihydrochelandine, 9-methoxy-10-hydroxy-norchelerythrine and other known alkaloids 6-methoxydihydrosanguinarine, 6-acetaldehyde-dihyrochelerythrine, dihydrosanguinaline and 10-methoxy boconoline had good inhibitory effects on MCF-7 cells of breast cancer with an IC50 lower than 20 µM.

The genus Cassia L.: Ethnopharmacological and phytochemical overview.

Nature gifts medicinal plants with the untapped and boundless treasure of active chemical constituents with significant therapeutic potential that makes these plants a beneficial source in the development of phytomedicines. Genus Cassia, with approximately 500 species, is a large group of flowering plants in the family Fabaceae. Cassia species are widely distributed throughout different regions mainly tropical Asia, North America, and East Africa. In the folk medicinal history, these plants are used as laxative and purgative agents. In the Ayurveda system of medicine, they are used to cure headache and fever. Cassia plants exhibit pharmacological activities at large scales such as antimicrobial, anticancer, antiinflammatory, antioxidant, hypoglycemic, hyperglycemic, antimutagenic, and antivirals. The phytochemical investigations of genus Cassia demonstrate the presence of more than 200 chemical compounds, including piperidine alkaloids, anthracene derivatives (anthraquinones), flavonoids, pentacyclic triterpenoids, sterols, phenylpropanoids, and γ-naphthopyrones. The literature illustrated anthraquinones and flavonoids as major secondary metabolites from this genus. However, some Cassia plants, with rich contents of anthraquinones, still show toxicology properties. As Cassia plants are used extensively in the herbal system of medicine, but only senna dosage forms have achieved the status of the pharmaceutical market as standard laxative agents. In conclusion, further investigations on isolating newer biologically active constituents, unknown underlying mechanisms, toxicology profiles, and clinical studies of Cassia species are needed to be explored. This review article specifies the systematic breach existing between the current scientific knowledge and the fundamentals for the marketization of genus Cassia products.

SRY-related high-mobility-group box 6 suppresses cell proliferation and is downregulated in breast cancer.

Breast cancer is one of the most common cancers endangering women's health. SRY-related high-mobility-group box 6 (SOX6) is associated with many cancers, though its role has not been reported in breast cancer. Here, we aimed to explore the expression and function of SOX6 in breast cancer. On the basis of the analysis of SOX6 in The Cancer Genome Atlas, Cancer Cell Line Encyclopedia and Genotype-Tissue Expression databases, we revealed that SOX6 was downregulated in breast cancer, and we verified the results at the cellular level by means of western blotting and quantitative real-time PCR. When SOX6 was overexpressed, the proliferation of breast cancer cells was inhibited, and apoptosis was promoted. Moreover, the methylation level of the SOX6 promoter in breast cancer was significantly higher than that in normal tissues. 5'-Aza-2'-deoxycytidine reversed the high level of methylation that was caused by decreased expression of SOX6. This evidence suggests that SOX6 is a tumor suppressor gene associated with breast cancer. This study could provide a new target for breast cancer treatment.

Cytotoxic Yohimbine-Type Alkaloids from the Leaves of Rauvolfia vomitoria.

Two new yohimbine-type monoterpene indole alkaloids, rauvines A and B, and six known derivatives were obtained from the leaves of R. vomitoria. The structures of rauvines A and B were determined by extensive spectroscopic analyses, 13 C-NMR, and ECD calculations. This is the first time to determine the absolute configurations of yohimbine-type N-oxides by quantum chemistry calculations (13 C-NMR and ECD calculations). All the isolates were tested for their cytotoxicity against five human cancer cell lines. Rauvine B showed moderate cytotoxicity on human MCF-7 breast, SWS80 colon, and A549 lung cancer cell lines with IC50 values of 25.5, 22.6, and 26.0 µM, respectively.

Monoterpene indole alkaloids with acetylcholinesterase inhibitory activity from the leaves of Rauvolfia vomitoria.

Seventeen monoterpene indole alkaloids, including seven new alkaloids (1-7) and ten known analogues (8-17), were isolated and identified from the leaves of R. vomitoria. The structures of new alkaloids were elucidated by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis. Rauvomitorine I (1) represents the first example of an unprecedented C22 yohimbine-type monoterpene indole alkaloid featuring a carboxymethyl at C-14. The exceedingly rare vobasenal (2-3) and affinisine oxindole (5-6) framework type alkaloids are first reported from the Rauvolfia genus. Most notably, the structure of vobasenal-type alkaloids (2-3) were first determined by single-crystal X-ray diffraction analyses. Alkaloids 1-17 were tested their cytotoxicity against five cancer cell lines, however, none of them showed significant cytotoxicity at a concentration of 40 µM. All the isolated alkaloids were evaluated their acetylcholinesterase (AChE) inhibitory activities. Alkaloid 3 exhibited significant anti-AChE activity with an IC50 value of 16.39 ± 1.41 µM and alkaloids 8 and 10 showed moderate anti-AChE activities whereas the others (2, 9, 13, and 17) were weak inhibitors. This is the first report of vobasenal-type alkaloids as AChE inhibitors, indicating this type of alkaloids may be important sources for the discovery of new AChE inhibitors. A preliminary structure-activity relationship for AChE inhibitory activities showed the presence of the N-methyl group in vobasenal-type alkaloids may be essential for anti-AChE activity. Further molecular docking studies of vobasenal-type alkaloids revealed that interaction with Trp133 and Trp86 residues at hydrophobic subsite are necessary for the AChE inhibitory activities. This study not only enriches the chemical diversity of alkaloids in Apocynaceae plants but also provides new potential leading compounds and versatile scaffolds for the design and development of new AChE inhibitors to treat AD.

Monoterpene indole alkaloids with diverse skeletons from the stems of Rauvolfia vomitoria and their acetylcholinesterase inhibitory activities.

Nine undescribed monoterpene indole alkaloids, rauvomitorine A-I, including an unprecedented C-9-methoxymethylene-sarpagine framework alkaloid, two rare suaveoline framework type alkaloids, and six yohimbine framework type alkaloids, as well as eleven known alkaloids, were isolated from the stems of Rauvolfia vomitoria Afzel. (Apocynaceae). The structures of the unreported alkaloids were elucidated by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis with Cu Kα radiation. Rauvomitorine A with an unreported framework type represents the first example of C-9-methoxymethylene-sarpagine alkaloids and its plausible biosynthetic pathway was proposed. All the isolated alkaloids were evaluated their acetylcholinesterase inhibitory (AChE) activities and cytotoxicity against five cancer cell lines and some of them exhibited potential anti-AChE activities with IC50 values ranging from 49.76 to 186.62 µM. Importantly, this is the first report of the AChE inhibitory activities on suaveoline framework type alkaloids, suggesting this type of alkaloids may be valuable sources for the discovery of AChE inhibitory agents. A preliminary structure-activity relationship for AChE inhibitory activities of the isolated alkaloids is also discussed, providing some clues to designing lead compounds for AChE inhibitors.

Hebecarposides A-K, antiproliferative lanostane-type triterpene glycosides from the leaves of Lyonia ovalifolia var. hebecarpa.

Eleven previously undescribed lanostane-type triterpene glycosides, hebecarposides A-K, were isolated from the leaves of Lyonia ovalifolia var. hebecarpa (Ericaceae), along with two known analogues, lyonifolosides L and O. The structures of hebecarposides A-K were established by extensive spectroscopic analysis and chemical methods, and the absolute configuration of C-24 in hebecarposides A and E was determined to be S and R, respectively, by a Mo2(OAc)4-induced electronic circular dichroism method. This is the first report of the presence of lanostane-type triterpene glycosides in L. ovalifolia var. hebecarpa. All compounds were evaluated for their antiproliferative activities against five cancer cell lines, SMMC-7721, HL-60, SW480, MCF-7, and A-549, and a normal epithelial cell line BEAS-2B, and none of them showed general cytotoxity to the normal cell line BEAS-2B. Interestingly, hebecarposides C, D, G, and K selectively inhibited the proliferation of HL-60 and SMMC-7721 cell lines, and hebecarposides C and D showed significant anti-proliferative activities against A-549 cell lines than the positive control, cis-platin. In addition, hebecarposides C and H exhibited more potent anti-proliferative activities against MCF-7 than cis-platin.

Zephycandidine A, the First Naturally Occurring Imidazo[1,2-f]phenanthridine Alkaloid from Zephyranthes candida, Exhibits Significant Anti-tumor and Anti-acetylcholinesterase Activities.

Zephycandidine A (1), the first naturally occurring imidazo[1,2-f]phenanthridine alkaloid, was isolated from Zephyranthes candida (Amaryllidaceae). The structure of 1 was elucidated by spectroscopic analyses and NMR calculation, and a plausible biogenetic pathway for zephycandidine A (1) was proposed. Zephycandidine A (1) exhibited significant cytotoxicity against five cancer cell lines with IC50 values ranging from 1.98 to 7.03 µM with selectivity indices as high as 10 when compared to the normal Beas-2B cell. Further studies suggested that zephycandidine A (1) induces apoptosis in leukemia cells by the activation of caspase-3, upregulation of Bax, downregulation of Bcl-2, and degradation of PARP expression. In addition, zephycandidine A (1) showed acetylcholinesterase (AChE) inhibitory activity, and the docking studies of zephycandidine A (1) and galanthamine (2) with AChE revealed that interactions with W286 and Y337 are necessary.

Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia.

Aberrant activation of the NOTCH signaling pathway is crucial for the onset and progression of T cell leukemia. Yet recent studies also suggest a tumor suppressive role of NOTCH signaling in acute myeloid leukemia (AML) and reactivation of this pathway offers an attractive opportunity for anti-AML therapies. N-methylhemeanthidine chloride (NMHC) is a novel Amaryllidaceae alkaloid that we previously isolated from Zephyranthes candida, exhibiting inhibitory activities in a variety of cancer cells, particularly those from AML. Here, we report NMHC not only selectively inhibits AML cell proliferation in vitro but also hampers tumor development in a human AML xenograft model. Genome-wide gene expression profiling reveals that NMHC activates the NOTCH signaling. Combination of NMHC and recombinant human NOTCH ligand DLL4 achieves a remarkable synergistic effect on NOTCH activation. Moreover, pre-inhibition of NOTCH by overexpression of dominant negative MAML alleviates NMHC-mediated cytotoxicity in AML. Further mechanistic analysis using structure-based molecular modeling as well as biochemical assays demonstrates that NMHC docks in the hydrophobic cavity within the NOTCH1 negative regulatory region (NRR), thus promoting NOTCH1 proteolytic cleavage. Our findings thus establish NMHC as a potential NOTCH agonist that holds great promises for future development as a novel agent beneficial to patients with AML.

N-methylhemeanthidine chloride, a novel Amaryllidaceae alkaloid, inhibits pancreatic cancer cell proliferation via down-regulating AKT activation.

We previously reported the isolation of a novel Amaryllidaceae alkaloid, N-methylhemeanthidine chloride (NMHC), from Zephyranthes candida, which exhibits potent cytotoxicity in a spectrum of tumor cells. However, the mechanism of action remains unclear. Using multiple cell lines derived from human pancreatic cancer, one of the most mortal and refractory human malignancies, we further studied the NMHC-mediated cytotoxicity and found that it induced drastic cytotoxicity in pancreatic cancer cells whereas an insignificant effect on a noncancerous cell line. The NMHC-mediated growth inhibition was more severe than the first-line chemotherapeutic agent gemcitabine, leading to cell cycle arrest, apoptotic death and decreased glycolysis. NMHC exerted its function through down-regulating AKT activation, and the ectopic expression of activated AKT rescued the growth inhibition. Consistently, NMHC injections in a pancreatic cancer xenograft model manifested the anti-tumor effect in vivo. Engrafted tumor cells underwent AKT attenuation and apoptotic death upon treatments. As such, we here demonstrate the AKT inhibition may be one of the mechanisms by which NMHC decreases tumor cell survival rate in vitro and in vivo. Our data thereby suggest that NMHC holds great promise as a potent chemotherapeutic agent against pancreatic cancer and sheds new light on obtaining such agents from natural products toward therapeutic purposes.