I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 11. Thermochemistry and kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 111. Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 A. Orbital symmetry considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 B. Stereochemical approach . . . . . . . . . . . . . . . . . . . . . . 97 IV. Scope and limitations . . . . . . . . . . . . . . . . 101 A. Substituted cyclohexenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 B. Norbornene derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 C. Other bridged systems . . . . . . . . . . . . . . . . . . . . . . . . . 114 D. Ortho-condensed systems . . . . . . . . . . 117 E. Intramolecular RDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 F. Heterocyclic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Retro-Diels-Alder reaction in mass spectrometry

Nine new alkaloids, melodinines M-U (1-9), and 11 known alkaloids were isolated from Melodinus suaveolens. The new structures were elucidated by extensive NMR and mass spectroscopic analyses and comparison to known compounds. All compounds were evaluated for their cytotoxicity against five human cancer cell lines. Compounds 6, 11, and 16 showed significant cytotoxicity.

Melodinines M-U, cytotoxic alkaloids from Melodinus suaveolens.

Eight new monoterpenoid indole alkaloids, alstoyunines A-H (1-8), along with 17 known analogues, were isolated from Alstonia yunnanensis. The structures of. the new alkaloids were established by means of extensive spectroscopic methods. Alstoyunines C (3), E (5), and F (6) showed selective inhibition of Cox-2 (>75%). Alstoyunine F (6) showed weak cytotoxicity against the human myeloid leukemia HL-60 (IC(50) = 3.89 mu M) and hepatocellular carcinoma SMMC-7721 (IC(50) = 21.73 mu M) cell lines.

Monoterpenoid Indole Alkaloids from Alstonia yunnanensis

While the characterization of the biosynthetic pathway of monoterpene indole alkaloids (MIAs) in leaves of Catharanthus roseus is now reaching completion, only two enzymes from the root counterpart dedicated to tabersonine metabolism have been identified to date, namely tabersonine 19-hydroxylase (T19H) and minovincine 19-O-acetyltransferase (MAT). Albeit the recombinant MAT catalyzes MIA acetylation at low efficiency in vitro, we demonstrated that MAT was inactive when expressed in yeast and in planta, suggesting an alternative function for this enzyme. Therefore, through transcriptomic analysis of periwinkle adventitious roots, several other BAHD acyltransferase candidates were identified based on the correlation of their expression profile with T19H and found to localize in small genomic clusters. Only one, named tabersonine derivative 19-O-acetyltransferase (TAT) was able to acetylate the 19-hydroxytabersonine derivatives from roots, such as minovincinine and horhammericine, following expression in yeast. Kinetic studies also showed that the recombinant TAT was specific for root MIAs and displayed an up to 200-fold higher catalytic efficiency than MAT. In addition, gene expression analysis, protein subcellular localization and heterologous expression in Nicotiana benthamiana were in agreement with the prominent role of TAT in acetylation of root-specific MIAs, thereby redefining the molecular determinants of the root MIA biosynthetic pathway. Finally, identification of TAT provided a convenient tool for metabolic engineering of MIAs in yeast enabling efficiently mixing different biosynthetic modules spatially separated in the whole plant. This combinatorial synthesis associating several enzymes from Catharanthus roseus resulted in the conversion of tabersonine in tailor-made MIAs bearing both leaf and root-type decorations.

A BAHD acyltransferase catalyzing 19-O-acetylation of tabersonine derivatives in roots of Catharanthus roseus enables combinatorial synthesis of monoterpene indole alkaloids.

By the end of the twentieth century, the interest in natural compounds as probable sources of drugs has declined and was replaced by other strategies such as molecular target-based drug discovery. However, in the recent times, natural compounds regained their position as extremely important source drug leads. Indole-containing compounds are under clinical use which includes vinblastine and vincristine (anticancer), atevirdine (anti-HIV), yohimbine (erectile dysfunction), reserpine (antihypertension), ajmalicine (vascular disorders), ajmaline (anti-arrhythmic), vincamine (vasodilator), etc. Monoterpene Indole Alkaloids (MIAs) deserve the curiosity and attention of researchers due to their chemical diversity and biological activities. These compounds were considered as an impending source of drug-lead. In this review 444 compounds, were identified from six genera belonging to the family Apocynaceae, will be discussed. These genera (Alstonia, Rauvolfia, Kopsia, Ervatamia, and Tabernaemontana, and Rhazya) consist of 400 members and represent 20% of Apocynaceae species. Only 30 (7.5%) species were investigated, whereas the rest are promising to be investigated. Eleven bioactivities, including antibacterial, antifungal, anti-inflammatory and immunosuppressant activities, were reported. Whereas cytotoxic effect represents 47% of the reported activities. Convincingly, the genera selected in this review are a wealthy source for future anticancer drug lead.

Chemical Diversity and Bioactivities of Monoterpene Indole Alkaloids (MIAs) from Six Apocynaceae Genera

Structures and absolute stereochemistry of (-)-echitoveniline, (-)-11-methoxyechitoveniline and (-)-11-methoxyechitovenedine—new indole alkaloids of

Structure and absolute stereochemistry of 19-epi-(+)-echitoveniline. A new indole alkaloid of the leaves of Alstonia venenata r.br.

Structure of echitoserpine, a new alkaloid of the fruits of Alstonia venenata

Structures and absolute stereochemistry of (-)-echitoveniline, (-)-11-methoxyechitoveniline and (-)-11-methoxyechitovenedine - new indole alkaloids of alstonia venenata r.br

B.N. Dinda

Papers

Structures and absolute stereochemistry of (-)-echitoveniline, (-)-11-methoxyechitoveniline and (-)-11-methoxyechitovenedine—new indole alkaloids of

Structure and absolute stereochemistry of 19-epi-(+)-echitoveniline. A new indole alkaloid of the leaves of Alstonia venenata r.br.

Structure of echitoserpine, a new alkaloid of the fruits of Alstonia venenata

Structures and absolute stereochemistry of (-)-echitoveniline, (-)-11-methoxyechitoveniline and (-)-11-methoxyechitovenedine - new indole alkaloids of alstonia venenata r.br