Synthesis and structure-activity relationship of lipo-diterpenoid alkaloids with potential target of topoisomerase IIα for breast cancer treatment.

Aconitine linoleate (11) isolated from the Aconitum sinchiangense W. T. Wang exhibited significant anti-tumor activity. Based on this, a series of novel lipo-diterpenoid alkaloids were synthesized and evaluated for their anticancer activities against MCF-7 and MCF-7/ADR cell lines. Seventeen compounds, including 18-20, 22, 24-32, 36, 39, 41-42 possessed higher anti-proliferative activities (IC50 < 20 µM) against MCF-7 cell lines, which were better than the reference drug etoposide (IC50 = 18.01 ± 1.64 µM), among which compound 24 (IC50 = 4.00 ± 0.30 µM) was found to be the most potent derivative, being 4.5-fold more active than etoposide. Meanwhile, eighteen compounds, including 18-22, 24, 26-32, 36, 38-39, 41-42 presented excellent activities (IC50 < 20 µM) against MCF-7/ADR cell lines, better than etoposide (IC50 = 35.48 ± 0.29 µM) and doxorubicin (IC50 = 67.61 ± 6.5 µM). The most potent compound (19) was 13.5- and 25.7-fold more active than etoposide and doxorubicin against MCF-7/ADR cell lines, respectively. The structure-activity relationship (SAR) studies indicated that the 3-OH, 8-lipo, 14-benzene ring, and nitrogen atom with proper alkaline are crucial elements for anti-proliferative activity of target lipo-diterpenoid compounds. The proper length, the double bonds or di-fluoro-substituted at C-8 fatty acid chain, the para-donating electron group on 14-benzene group, and 13-OH are all favorable for the enhancement of anti-proliferative activities. In conclusion, the introduction of the 8-lipo group into aconitine leads to significant increase of anti-proliferative activity against MCF-7 and MCF-7/ADR cells, which suggests these kinds of lipo-alkaloids are powerful and promising antitumor compounds for breast cancer, especially for drug-resistant breast cancer.

An unexpected Lewis acid-mediated structural conversion of a Euphorbia Diterpene: From a Lathyrane skeleton to diterpene pseudo-alkaloids.

Three types of new Euphorbia diterpene pseudo-alkaloids possessing 5/6/7/3 (1), 5/6/6/4 (2-5), and 5/7/7/4 (6-7) fused ring skeletons were obtained through an unexpected BF3·Et2O/CH3CN-mediated structural conversion and amination of lathyrane diterpene (Euphorbia factor L1), in which the solution acetonitrile had been introduced into the Euphorbia diterpene as a nitrogen source and tandem amination/oxirane-opening (cyclopropane-opening)/oxa-Michael addition reaction was involved in the conversion. The structures of new Euphorbia diterpene pseudo-alkaloids were elucidated by a combination of spectroscopic data and single crystal X-ray diffraction analysis. The basic skeletons of Euphorbia diterpene pseudo-alkaloids 1 and 2-5 could fall into the structural types of euphoractine B and euphoractine A diterpenes, respectively, suggesting the possible biogenetic pathway relationship between lathyrane diterpene with euphoractines A and B types diterpenes. Pseudo-alkaloids 1-7 did not show any potential cytotoxicity against several tumor cell lines.

Isolation and identification of two pairs of cytotoxic diterpene tautomers and their tautomerization mechanisms.

Discovering anticancer drugs that do not have adverse side effects has been a developing research field worldwide in recent decades. In this work, four previously undescribed cytotoxic diterpenoids were isolated from the aerial parts of Isodon excisoides. Interestingly, these four diterpenoids were two pairs of tautomers that were first reported in plants. Their structures were further elucidated using various spectroscopic methods. The tautomerization phenomenon and mechanism for these two pairs of tautomers were emphatically described. The theoretical simulation results indicated that the diterpene tautomerization is greatly related to certain factors, including the existence of a transition state, the change of bond length and the level of conversion energy; the tautomerization for the two pairs of tautomers is mainly caused by proton transfer. For bioassays, the cytotoxicities of the tautomers against five human cancer cell lines were also investigated. The results indicated that each of the four diterpenoids showed significant cytotoxicity in at least three cell lines and could serve as potential anticancer agents for further investigation.

Cytotoxic Effects of Diterpenoid Alkaloids Against Human Cancer Cells.

Diterpenoid alkaloids are isolated from plants of the genera Aconitum, Delphinium, and Garrya (Ranunculaceae) and classified according to their chemical structures as C18-, C19- or C20-diterpenoid alkaloids. The extreme toxicity of certain compounds, e.g., aconitine, has prompted a thorough investigation of how structural features affect their bioactivities. Therefore, natural diterpenoid alkaloids and semi-synthetic alkaloid derivatives were evaluated for cytotoxic effects against human tumor cells [A549 (lung carcinoma), DU145 (prostate carcinoma), MDA-MB-231 (triple-negative breast cancer), MCF-7 (estrogen receptor-positive, HER2-negative breast cancer), KB (identical to cervical carcinoma HeLa derived AV-3 cell line), and multidrug-resistant (MDR) subline KB-VIN]. Among the tested alkaloids, C19-diterpenoid (e.g., lipojesaconitine, delcosine and delpheline derivatives) and C20-diterpenoid (e.g., kobusine and pseudokobusine derivatives) alkaloids exhibited significant cytotoxic activity and, thus, provide promising new leads for further development as antitumor agents. Notably, several diterpenoid alkaloids were more potent against MDR subline KB-VIN cells than the parental drug-sensitive KB cells.

Prenylated Indole Diterpene Alkaloids from a Mine-Soil-Derived Tolypocladium sp.

Ten new prenylated indole diterpene alkaloids, tolypocladin A-J (1-10), including four chlorinated metabolites, have been isolated from a culture of a mine-soil-derived fungus, Tolypocladium sp. XL115. The structures and absolute configurations of 1-10 were determined by spectroscopic analysis, ECD calculations, and comparison with known compounds. Compounds 1 and 8 displayed significant antimicrobial activities. In addition, compound 1 also showed weak cytotoxic activity against all tested human cancer cell lines and suppressed the growth and viability of the patient-derived HCC cells T1224.

Mechanism of Action of the Cytotoxic Asmarine Alkaloids.

The asmarines are a family of cytotoxic natural products whose mechanism of action is unknown. Here, we used chemical synthesis to reverse engineer the asmarines and understand the functions of their individual components. We found that the potent asmarine analog "delmarine" arrested the mammalian cell cycle in the G1 phase and that both cell cycle arrest and cytotoxicity were rescued by cotreatment with ferric and ferrous salts. Cellular iron deprivation was clearly indicated by changes in iron-responsive protein markers, and cytotoxicity occurred independently of radical oxygen species (ROS) production. Chemical synthesis allowed for annotation of the distinct structural motifs required for these effects, especially the unusual diazepine, which we found enforced an iron-binding tautomer without distortion of the NCNO dihedral angle out of plane. With this information and a correlation of cytotoxicity with logP, we could replace the diazepine by lipophilic group appendage to N9, which avoided steric clash with the N6-alkyl required to access the aminopyridine. This study transformed the asmarines, scarce marine metabolites, into easily synthesized, modular chemotypes that may complement or succeed iron-selective binders in clinical trials and use.