Rational design and structure-activity relationship studies reveal new esterified C20-diterpenoid alkaloid analogues active against MCF-7 human breast cancer cells.

Although various diterpenoid alkaloids have been evaluated recently for antiproliferative activity against human tumor cell lines, little information is available regarding the antiproliferative effects of C20-diterpenoid alkaloids against MCF-7 cells. Six new diterpenoid alkaloid derivatives (13, 14, 22, 23, 25, 26) were prepared by C-11 and 15 esterification of kobusine (6). The natural parent alkaloid 6 and all synthesized derivatives (7 - 27, 12a, 15a, 15b, 18a, 18b) were evaluated for antiproliferative activity against MCF-7 cells. The structure-based design strategy resulted in an initial lead derivative, 11,15-dibenzoylkobusine (7; IC50 8.6 µM). Subsequent synthesized 11,15-diacylkobusine derivatives (9, 16, 20, 21, 23, 25, and 26) showed substantially increased suppressive effects against the MCF-7 cell line (IC50 2.3-4.4 µM). In contrast, parent alkaloid 6, two 11-acylkobusine derivatives (15a, 18a), and two 15-acylkobusine derivatives (15b, 18b) showed no effect. 11,15-Diacylation appears to be critical for producing antiproliferative activity in this alkaloid class and could introduce a new avenue in overcoming breast cancer cell proliferation using natural product derivatives. In a preliminary mechanism of action study, representative derivatives (5, 8, 9, and 17) decreased cyclin D1 mRNA expression.

Bioactivity inspired C19-diterpenoid alkaloids for overcoming multidrug-resistant cancer.

The pharmacological activities of C19-diterpenoid alkaloids are related to their basic skeletons (e.g., aconitine-type or lycoctonine-type). Also, few studies have been reported on the chemosensitizing effects of diterpenoid alkaloids. Consequently, this study was aimed at determining the chemosensitizing effects of synthetic derivatives of lycoctonine-type C19-diterpenoid alkaloids on a P-glycoprotein (P-gp)-overexpressing multidrug-resistant (MDR) cancer cell line KB-VIN. The acyl-derivatives of delpheline and delcosine showed moderate cytotoxicity against chemosensitive cancer cell lines. Among non-cytotoxic synthetic analogs (1-14), several derivatives effectively and significantly sensitized MDR cells by interfering with the drug transport function of P-gp to three anticancer drugs, vincristine, paclitaxel, and doxorubicin. The chemosensitizing effect of derivatives 2, 4, and 6 on KB-VIN cells against vincristine were more potent than 5 µM verapamil, and derivatives 4 and 13 were more effective than 5 µM verapamil for paclitaxel. Among them, 2 in particular increased the sensitivity of KB-VIN cells to vincristine by 253-fold.

Eleven new C19-diterpenoid alkaloids from Delphinium elatum cv. Pacific Giant.

Diterpenoid alkaloids, the main components of plants of the genera Aconitum, Delphinium, and Garrya, are a group of natural products with notable chemical properties and biological activities. Several C19-diterpenoid alkaloid components from Delphinium elatum cv. Pacific Giant, as well as their derivatives, exhibited cytotoxic activity against lung, prostate, cervical, and vincristine-resistant cervical cancer cell lines. In the current phytochemical investigation on the seeds of D. elatum cv. Pacific Giant, eleven new C19-diterpenoid alkaloids, elapaciline (1), meladine (2), melapacitine (3), iminoeladine (4), 19-oxopaciline (5), 19-oxopacinine (6), N-deethyldelpheline (7), N-deethylpacinine (8), N-deethyl-19-oxoeladine (9), N-deethyl-N-formyleladine (10), and N-deethyl-N-formyldelpheline (11), together with 15 known C19-diterpenoid alkaloids were isolated. Their structures were elucidated by extensive spectroscopic methods including NMR (1D and 2D), IR, and MS (HRMS). Three known diterpenoid alkaloids, 6-dehydrodelcorine (12), delelatine (23), and 6-dehydroeldelidine (24), were isolated for the first time from this plant. Six of the new C19-diterpenoid alkaloids (2, 4-7, and 11) and three of the known diterpenoid alkaloids (18, 23, and 24) were evaluated for cytotoxic activity against five human tumor cell lines.

Dimensions of women's empowerment on access to skilled delivery services in Nepal.

BACKGROUND: Each day, approximately 810 women die during pregnancy and childbirth and 94% of the deaths take place in low and middle income countries. Only 45% of the births in South Asia are attended by skilled professionals, which is lower than that in other Asian regions. Antenatal and postnatal care received from skilled providers can help prevent maternal and neonatal mortality by identifying pregnancy-related complications. Women's empowerment is considered to be a significant determinant of maternal health care outcomes; however, studies on the contextual influences of different dimensions of empowerment in Nepal are relatively limited. Therefore, this study analyzed nationwide survey data to examine the influence of women's economic empowerment, sociocultural empowerment, familial/interpersonal empowerment and media and information technology empowerment on accessing skilled delivery services among the married women in Nepal. METHODS: This study examined the influence of women's empowerment on skilled delivery services among married women (n = 4400) aged 15-49 years using data from the 2016 Nepal Demographic and Health Survey. Descriptive analysis and binary logistic regression analysis were employed to analyze the data. RESULTS: Significant associations were found between women's media and information technology empowerment, economic empowerment and sociocultural empowerment and access to skilled birth attendants. Specifically, the education of women, their occupation, owning a bank account, media exposure, and internet use were significantly associated with the use of skilled birth attendants. CONCLUSION: Focusing on women's access to media and information technology, economic enhancement and education may increase the use of skilled birth attendants in Nepal.

Cytotoxic diterpenoid alkaloid from Aconitum japonicum subsp. subcuneatum.

We explored new cytotoxic C19-diterpenoid alkaloid, lipojesaconitine (1), from rhizoma of Aconitum japonicum THUNB. subsp. subcuneatum (NAKAI) KADOTA. Two additional non-cytotoxic new C19-diterpenoid alkaloids, 10-hydroxychasmanine (2) and 3-hydroxykaracoline (3), together with eight known C19- and C20-diterpenoid alkaloids (4-11) were also isolated. Their structures were elucidated by extensive spectroscopic methods including NMR (1D and 2D), IR, and MS (HRMS). Six known diterpenoid alkaloids, foresticine (5), neolinine (6), aconicarchamine A (7), 9-hydroxynominine (8), kobusine (9), and torokonine (10), were isolated for the first time from A. japonicum subsp. subcuneatum. Alkaloid 1 showed cytotoxicity with IC50 values ranging from 6.0 to 7.3 µM against four human tumor cell lines, except a multidrug-resistant subline, suggesting that 1 was likely exported by P-glycoprotein.

Selenium supplementation in HIV-infected individuals: A systematic review of randomized controlled trials.

BACKGROUND & AIM: HIV infection has been linked to selenium deficiency which, in turn, is thought to be associated with a high risk of tuberculosis and mortality in HIV-infected patients. Furthermore, several trials have reported the beneficial effects of selenium supplementation in patients with HIV. However, the evidence remains inconclusive. Our study aimed to investigate whether daily selenium supplementation in patients infected with HIV delays the progression of HIV infection. METHODS: A systematic review was performed using EMBASE and Medline databases from January 2000 to June 2018. We included randomized clinical trials in adults comparing selenium with placebo and reporting outcomes including its effect on HIV viral load and cluster of differentiation 4 cell count (CD4). RESULTS: Six out of the 507 retrieved articles that met the inclusion criteria were used in this review. Reviewed studies show that daily supplementation with 200 µg selenium may improve the rate of cluster of differentiation 4 (CD4) count. The length of selenium supplementation and follow-up varied from 9 to 24 months. Supplements were well tolerated in all reviewed studies. Whether daily selenium supplementation in HIV-infected persons suppresses HIV-infection requires further investigation as existing data are heterogeneous. CONCLUSIONS: We found some clinical evidence that selenium supplementation can delay CD4 decline in HIV-infected patients, thus prolonging the onset of AIDS. However, we did not find quantifiable evidence that selenium supplementation suppresses or reduces HIV viral load.

Structure-activity relationships and evaluation of esterified diterpenoid alkaloid derivatives as antiproliferative agents.

Diterpenoid alkaloids with remarkable chemical properties and biological activities are frequently found in plants of the genera Aconitum, Delphinium, and Garrya. However, little information has been reported on the antiproliferative effects of the diterpenoid alkaloid constituents of Aconitum and Delphinium plants. C-1 and 14 esterifications of delcosine (1) were carried out to provide 39 new diterpenoid alkaloid derivatives (3-14, 16-29, 3a-7a, 9a, 13a, 13b, 14a, 14b, 16a, 17a, 24a, 35a). Selected compounds (3-14, 16-29, 3a-7a, 9a, 13a, 13b, 14a, 14b, 16a, 17a, 24a, 35a) were evaluated for antiproliferative activity against three to five human tumor cell lines including triple-negative breast cancer (TNBC) and P-glycoprotein (P-gp) overexpressing multidrug-resistant (MDR) subline. Several newly synthesized delcosine derivatives (6, 7, 13, 13a, 13b) showed substantial suppressive effects against all human tumor cell lines tested. In contrast, the natural alkaloids (1, 31, 33) showed no effect. Most of the active compounds were delcosine derivatives with two specific substitution patterns-C-1 and C-1,14. In particular, 1-acyldelcosine derivative (5-7) displayed more potency than 1,14-diacyldelcosine derivatives (5a-7a). These acylated alkaloid derivatives caused accumulation of TNBC cells at sub-G1 within 24 h. 1-Acylation of 1 appears to be critical for producing antiproliferative activity in this alkaloid class and a means to provide promising new leads for further development into antitumor agents.

Anti-stress and Antioxidant Effects of Non Centrifuged Cane Sugar, Kokuto, in Restraint-Stressed Mice.

Stress is a part of everyday life, but excessive stress can be related to diverse diseases. Recently, oral intake of a non-centrifuged cane sugar, Kokuto, was reported to produce potential anti-stress effects in humans. However, the molecular components associated with the anti-stress property of Kokuto remain mostly unknown. Therefore, we focused on the non-sugar component (NSC) fractions of Kokuto, and investigated how serum corticosterone level (used as a stress marker) and antioxidant activity were affected in restraint-stressed mice treated with NSC fractions obtained from the elusion on HP-20 resin with 25%, 50%, 75%, and 100% aqueous methanol (MeOH) solutions. Among the four NSC fractions, the 50% MeOH fraction showed a high content of phenolic compounds and high antioxidant activity. Moreover, oral administration of the 50% MeOH fraction suppressed both corticosterone secretion into the serum and reduction of antioxidant activity in serum and liver in restraint-stressed mice. Component analysis of the 50% MeOH fraction identified five antioxidative phenolic compounds: p-hydroxybenzaldehyde, p-hydroxyacetophenone, schaftoside, isoschaftoside, and p-coumaric acid. Phenolic compounds detected in the NSC fractions of Kokuto might contribute to the anti-stress property of Kokuto. In addition, this research provides more understanding of potential health benefits offered by the constituents of Kokuto.

Serum selenium levels in tuberculosis patients: A systematic review and meta-analysis.

INTRODUCTION: Tuberculosis (TB) is associated with increased mortality. The high risk of micronutrients deficiency, including selenium, in TB patients is of great concern because it increases the risk of death. However, it is not clear whether selenium supplementation could improve the treatment outcomes in TB patients. We conducted a systematic review and meta-analysis to provide an update on the existing evidence about low selenium levels in TB patients. METHODS: In this systematic review and meta-analysis, EMBASE, Medline and the International Journal of Tuberculosis and Lung Disease were searched to identify observational studies on selenium and TB published up until April 2018. Studies comparing blood selenium levels in TB patients to controls were included. Data extraction was performed by two investigators. The quality of the studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Random effects analysis was performed to calculate the pooled effect size and 95% confidence interval (CI). RESULTS: Of the 605 studies initially identified, only six were eligible. Of them, four were carried out in Asia, and one each in Africa and South America. The random pooled effect size was 1.6 (CI: 0.9, 2.4). This means that the probability is 160% for an individual with TB to have low levels of selenium as compared to an individual without TB. Heterogeneity across the studies was substantial (I2 = 95.1%). Potential sources of heterogeneity included study design and selenium measurement methods. CONCLUSION: Our review provides compelling evidence that serum selenium is lower in TB patients as compared with controls. Therefore, it is advisable to individually assess selenium status in TB patients and decide whether selenium supplement is needed or not.

Extended aroma extract dilution analysis profile of Shiikuwasha (Citrus depressa Hayata) pulp essential oil.

Shiikuwasha pulp is an important raw material for producing citrus essential oils. The volatile aroma composition of pulp essential oil was evaluated using gas chromatography (GC) methods, and its aroma profile was assessed using GC-olfactometry with an extended aroma extract dilution analysis (AEDA) technique in regard to alterations of odor strength and sensorial perception throughout serial dilution steps. The essential oil comprised a mixture of 55 aroma compounds, including monoterpene hydrocarbon, sesquiterpene hydrocarbon, alcohol, aldehyde, ester, and oxide compounds. The predominant compounds were limonene [57.36% (4462.80 mg/100 g of pulp)] and γ-terpinene [25.14% (1956.21 mg/100 g of pulp)]. However, linalool was identified as one of the key aroma components providing the highest flavor dilution factor in AEDA, whilst three sesquiterpene hydrocarbons (δ-elemene, germacrene B, and bicyclosesquiphellandrene) and two esters (heptyl acetate and decyl acetate) had superior relative flavor activities. The extended AEDA profile identified variations in assessed odor perceptions, intensity, and duration of aroma components over dilution, whereas the 12 most odor-active compounds showed comparable odor strengths.

Four new diterpenoid alkaloids from Aconitum japonicum subsp. subcuneatum.

Diterpenoid alkaloids with remarkable chemical properties and biological activities are frequently found in plants of the genera Aconitum, Delphinium, and Garrya. Accordingly, several diterpenoid alkaloid constituents of Aconitum and Delphinium plants as well as their derivatives exhibited cytotoxic activity against lung, prostate, nasopharyngeal, and vincristine-resistant nasopharyngeal cancer cell lines. Four new C19-diterpenoid alkaloids, 14-anisoyllasianine (1), 14-anisoyl-N-deethylaconine (2), N-deethylaljesaconitine A (3), and N-deethylnevadensine (4), together with 17 known C19- and C20-diterpenoid alkaloids, were isolated in a phytochemical investigation of rhizoma of Aconitum japonicum THUNB. subsp. subcuneatum (NAKAI) KADOTA. Their structures were elucidated by extensive spectroscopic methods including NMR (1D and 2D), IR, and MS (HRMS). Eight known diterpenoid alkaloids, lipoaconitine, lipomesaconitine, aconine, nevadenine, talatisamine, nevadensine, ryosenamine, and dehydrolucidusculine, were isolated the first time from A. japonicum subsp. subcuneatum. Three of the new C19-diterpenoid alkaloids (1, 3, 4) and six of the known diterpenoid alkaloids were evaluated for cytotoxic activity against five human tumor cell lines.

Comparison of the inhibitory effects of delphinidin and its glycosides on cell transformation.

Although anthocyanins are major forms distributed in many plant foods and promising as chemopreventive source, many molecular data are obtained from anthocyanidins, showing their low bioavailability. This study aims to clarify the inhibitory effects of delphinidin glycosides on cell transformation comparing them to those of delphinidin. Screening data revealed that delphinidin 3-sambubioside could directly bind to MAPK/ERK kinase 1. Affinity assay data confirmed that delphinidin 3-sambubioside had higher binding affinity to MAPK/ERK kinase 1 than ERK1/2 and B-Raf. Colony assay data further demonstrated that delphinidin 3-sambubioside inhibited 12-O- tetradecanoylphorbol-13-acetate-induced phosphorylation of MAPK/ERK kinase 1 and sequentially suppressed cell transformation. All of these effects caused by delphinidin 3-sambubioside were weaker than those by its aglycon, delphinidin. Our data suggested that the weaker anti- transformation activity of delphinidin glycosides compared to that of their aglycon is due to lower binding affinity to the target molecule MAPK/ERK kinase 1.

Production of sophorolipids from non-edible jatropha oil by Stamerella bombicola NBRC 10243 and evaluation of their interfacial properties.

To facilitate the development of bio-based chemicals from renewable and inexpensive natural resources, we sought to produce biosurfactants using non-edible jatropha oil. Twenty yeasts known to produce biosurfactants were tested in this study, and Stamerella bombicola NBRC 10243 was found to use jatropha oil efficiently to produce sophorolipids (SLs) as a mixture of lactone-form SL (L-SL) and acid-form SL (A-SL). Under culture conditions using rice bran as the source of organic nutrients, the yield of SLs reached 122.6 g/L in 5-L jar fermentors after 9 d in culture. HPLC analysis of the culture medium showed that the levels of phorbol esters (PEs), major toxic components of the oil, decreased markedly with an increase in culture time, suggesting that the yeast degrades PEs. Although the SLs obtained by solvent extraction of the culture medium contained a small amount of PEs, the sodium salt of A-SL (A-SL-Na) obtained by alkaline treatment (5N NaOH, 80°C) showed no PE peaks upon HPLC analysis. A-SL-Na had excellent surface activity with low CMC (9.0×10⁻4 M) and γ(CMC) (29.6 mN/m), which are lower than that of sodium dodecyl sulfate (SDS). The solubilizing ability of A-SL-Na toward for octanoic acid ([octanoic acid]/[A-SL-Na]) was found to be 2.0, which is half that of SDS. Our findings should help improve SL production from non-edible feedstock and broaden the use of promising bio-based surfactants.

Antioxidant activity of sugarcane molasses against 2,2'-azobis(2-amidinopropane) dihydrochloride-induced peroxyl radicals.

Sugarcane molasses is a rich source of antioxidant materials with peroxyl radical scavenging effects. To explore the potent antioxidant activity of sugarcane molasses against 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced peroxyl radicals, 7 methanolic fractions of sugarcane molasses (F1-F7) were separated via bioassay-guided fractionation and evaluated by oxygen radical absorbance capacity (ORAC), cellular antioxidant activity (CAA), and oxidative DNA damage protective activity assays. The ORAC values of sugarcane molasses fractions ranged from 4399 to 6,266 µmol TE/g, whilst the EC50 values for CAA ranged from 3.7 to 5.9 µg/ml. Moreover, it was found that sugarcane molasses fractions, particularly F6 and F7, could protect against oxidative DNA damage caused by peroxyl radicals at an effective concentration of 100 µg/ml. Ten phenolic constituents were identified in the fractions, including known antioxidative compounds, viz., schaftoside, isoschaftoside, ferulic acid, p-coumaric acid, and p-hydroxybenzaldehyde.

Screening of medicinal and edible plants in Okinawa, Japan, for enhanced proliferative and collagen synthesis activities in NB1RGB human skin fibroblast cells.

To identify plants with bioactive potential for skin care, methanol extracts of 56 plant parts from 47 medical and edible plants cultivated in Okinawa were tested for their proliferative effects on NB1RGB skin fibroblast cells. Extracts from six plants, Bischofia javanica, Colocasia esculenta, Melaleuca alternifolia, Piper angustifolia, Jasminum sambac, and Curcuma longa, showed higher NB1RGB cell proliferation activity (>10%) than the control, at various concentrations. Among the six extracts, only the C. longa extract caused an increase in collagen synthesis in NB1RGB cells, as compared to treatment with the positive control, ascorbic acid (AsA). Expression of the collagen synthesis marker, transforming growth factor-ß1, was higher after treatment with the C. longa extract than with AsA.

The composition of volatile aroma components, flavanones, and polymethoxylated flavones in Shiikuwasha (Citrus depressa Hayata) peels of different cultivation lines.

Citrus peels are important sources of various pleasant aroma compounds and valuable bioactive substances. To investigate differences in the composition and content of Shiikuwasha (Citrus depressa Hayata) peels from different cultivation lines, the composition of volatile aroma components, flavanones, and polymethoxylated flavones (PMFs) in four Shiikuwasha cultivation lines was examined. The composition of volatile aroma components in cold-pressed extracts of Shiikuwasha peels was analyzed using gas chromatography-flame ionization detection and gas chromatography-mass spectrophotometry. The extracts contained mainly monoterpene hydrocarbons (93.40-97.25%), including limonene (46.52-68.26%) and γ-terpinene (21.48-30.52%). Differences in the composition of volatile aroma compounds in the Shiikuwasha cultivation lines were revealed using principal component analysis. Additionally, the composition of flavanones and PMFs was determined using high-performance liquid chromatography methods. Neohesperidin (96.58%) was the predominant flavanone in 'Izumi kugani' peel, while the other peels had high hesperidin contents (89.26-98.66%). Moreover, the PMFs of Shiikuwasha peels were composed of nobiletin (56.74-64.77%) and tangeretin (23.17-34.70%).

Volatile aroma components and antioxidant activities of the flavedo peel extract of unripe Shiikuwasha (Citrus depressa Hayata).

UNLABELLED: The flavedo peel extracts of unripe Shiikuwasha (Citrus depressa Hayata) fruits were extracted using steam distillation (SD) or a cold-press (CP) system. Volatile aroma content and composition were determined using gas chromatography (GC) and each compound was identified using gas chromatography-mass spectrophotometry (GC-MS). The major constituents of the extracts were monoterpene hydrocarbons (91.75-93.75%[709.32-809.05 mg/100 g of fresh flavedo peel]) including limonene (43.08-45.13%[341.46-379.81 mg/100 g of fresh flavedo peel]), γ-terpinene (27.88-29.06%[219.90-245.86 mg/100 g of fresh flavedo peel]), and p-cymene (8.13-11.02%[61.47-97.22 mg/100 g of fresh flavedo peel]). The extraction process used was determined to be a decisive factor that affects the composition of key citrus aroma components, as well as the antioxidant activities of the Shiikuwasha fruit. Antioxidant capabilities of the extracts were examined by assay of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity and ß-carotene bleaching inhibition. The cold-press extraction system may better retain the total phenolic content of the flavedo peel and display superior antioxidant activities, compared to the steam distillation extraction method. PRACTICAL APPLICATION: Shiikuwasha (Citrus depressa Hayata) is a type of small citrus fruit, and has been used as raw material for beverage and food additive productions in Japan. It had a unique aroma composition in which the limonene content of its peels is lower than that of other commonly known citrus peels. The present study detailed the volatile aroma composition, as well as antioxidant capabilities of Shiikuwasha peel extracts of different extraction methods, that are cold-press and steam distillation methods. The results of this study may provide a basis for selection of Shiikuwasha peel extracts in food industry for citrus flavor production.

Aconitum C20-diterpenoid alkaloid derivatives regulate the growth and differentiation of cord blood derived human hematopoietic stem/progenitor cells.

The pharmacological activity of Aconitum alkaloids depends on their fundamental structure. While C19-norditerpenoid alkaloids present significant toxicity to the central nervous system, C20-diterpenoid alkaloids have reduced toxicities. However, there is little information regarding the precise pharmacological properties of C20-diterpenoid alkaloids. C20-diterpenoid alkaloid derivatives have explicit structure-activity relationships targeting various tumor cells, which depend on the C11-substrate. However, the present study showed that C6-derivatives additively or synergistically sustained proliferation of CD34⁺ hematopoietic stem/progenitor cells derived from the placental/umbilical cord blood. It revealed that identical structures belonging to C20-diterpenoid alkaloids surprisingly have opposing proliferative effects depending on the derivatization sites (C6 versus C11).

Recent Progress of Research on Herbal Products Used in Traditional Chinese Medicine: the Herbs belonging to The Divine Husbandman's Herbal Foundation Canon ( Shén Nóng Ben Cǎo Jing).

This article will review selected herbal products from Chinese Materia Medica that are used in Traditional Chinese Medicine. The herbs come from the upper, middle, and lower class medicines as listed in The Divine Husbandman's Herbal Foundation Canon ( Shén Nóng Ben Cǎo Jing). The review will focus on the active constituents of the herbs and their bioactivities, with emphasis on the most recent progress in research for the period of 2003 to 2011.

Structure-activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells.

The cytotoxicity of three alkaloids from the roots of Aconitum yesoense var. macroyesoense as well as 36 semi-synthetic C(20)-diterpenoid atisine-type alkaloid derivatives against A549 human lung carcinoma cells was examined. Ten acylated alkaloid derivatives, pseudokobusine 11-veratroate (9), 11-anisoate (12), 6,11-dianisoate (14), 11-p-nitrobenzoate (18), 11,15-di-p-nitrobenzoate (22), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate (27), and kobusine 11-p-trifluoromethylbenzoate (35), 11-m-trifluoromethylbenzoate (36) and 11,15-di-p-nitrobenzoate (39), exhibited cytotoxic activity, and 11,15-dianisoylpseudokobusine (16) was found to be the most potent cytotoxic agent. Their IC(50) values against A549 cells ranged from 1.72 to 5.44 µM. In the occurrence of cytotoxic effects of atisine-type alkaloids, replacement by an acyl group at both C-11 and C-15 resulted in the enhancement of activity of the parent alkaloids compared to that from having hydroxy groups at this position, and the presence of a hydroxy group at the C-6 position was required for the cytotoxic effects. These acylated alkaloid derivatives inhibit cell growth through G1 arrest.