Phytochemical and Pharmacological Properties of the Genus Melodinus – A Review

Melodinus is an important genus comprising of approximately 53 species of medicinal plants (Apocynaceae). Some species have been used in Chinese folk medicine for the treatment of meningitis in children, rheumatic heart diseases, and diuresis, as well as a decongestive against migraine and sinusitis. This paper is a review of the literature up to May 2015 and describes 263 compounds from 69 articles, and includes chemical constituents isolated from Melodinus, mainly indole alkaloids, quinoline alkaloids, dimeric alkaloids, terpenoids and other compounds. It is also hoped that an overview of their cytotoxic characteristics will further the development of new anti-cancer agents. African Journal Online, Bioline International, Open-J-Gate and Pharmacy Abstracts


INTRODUCTION
Melodinus is a genus of ca. 53 species in the family Apocynaceae, mainly distributed in tropical and subtropical Asia and from Oceania to the Pacific coast. Among them, ca. 11 species occur in South China, Southwest China and Taiwan [1]. Some species, such as M. suaveolens and M. henyri have been used in Chinese folk medicine for the treatment of meningitis in children, rheumatic heart diseases, diuresis, bone fracture and so on [2,3]. M. scandens is used as a decongestive, against migraines, sinusitis and otitis [4]. In Australia, an aq extract of M. australis, when injected into a dog, produced a sharp drop in blood pressure, accompanied by an increase in the depth of respiration and decrease in rate [5]. Current crude alkaloid mixtures and purified alkaloids from some Melodinus species have demonstrated antitumor and antibacterial activities [6,7]. Many characteristic melodinus alkaloids, such as meloscine, epimeloscine, scandine and vincadifformine, had for a long time attracted great interest of synthetic organic chemists as challenging targets due to their marked diversity and complicated architectures [8,9,10] And more than twenty alkaloids were reviewed from the genus Melodinus by Sevenet et al [11]. About 14 alkaloids can be classified into the melodan skeleton and its rearranged version and derived from 18, 19-didehydrotabersonine as parent compound in the plant family Apocynaceae [12] Recently, much attention has been paid to Melodinus plants to search active melodinus alkaloids. Extensive studies of the Melodinus genus have led to the identification of several novel alkaloids. Only 22 species of the genus have been chemically investigated and provided an array of structurally interesting indole alkaloids, quinoline alkaloids, dimeric indole alkaloids, diterpenoids, triterpenes and others compounds over the past few decades. Some compounds show cytotoxic and anti-inflammatory activities. In this paper, we summarize phytochemistry and pharmacological activities of the Melodinus species so as to collate the existent information on this plant.

PHYTOCHEMICAL CONSTITUENTS
By the deadline of MAY 2015, phytochemical studies on this genus led to the isolation of 263 compounds. Their structures are shown below and their names, the corresponding plant sources are collected. As can be seen, indole alkaloids are the dominant constituents within this genus.

Alkaloids
Plants of the genus Melodinus (Apocynaceae) have been proven to be good sources of alkaloids. This genus has been regarded as a rich source of monoterpenoid indole alkaloids, which originated from the condensation of tryptophan with secologanin. We now list 252 alkaloids which were obtained from the genus Melodinus. The structural characters and relationships of the major Melodinus alkaloid groups are discussed.

Tabersonine-group
This stereochemical series was more commonly encountered in the tabersonine group, as indicated in structures 20-55 (Table 2, Figure 2), respectively. The simple tabersonine derivatives   were identified as an acetonyl derivative of tabersonine by the NMR from M. tenuicaudatus [29]. And melotenine A (55), an unprecedented skeleton with a 6/5/5/6/7 pentacyclic rearranged ring system, which have been derived from tabersonine, was also isolated [41].

Vindolinine-type
This type was a small group with eleven alkaloids, 56-66 (Table 3, Fig 3), which contained a C (2)-C (19) bond in an aspidospermine ring from Melodinus spps. All of them expect compound 66 belong to the five pair of epimers and their names, the corresponding plant sources and the reference are collected in Table  3.
And the structure of stereochemistry by UV, IR, NMR and X-ray [65,66].  and melodinhenine E-F (198, 199) obtained from M. fusiformis, M. hemsleyanus, M. henryi and M. oblongus [25,28,63]. On the structure elucidation of the main alkaloids of M. acutiflorus, which led to a revision of the structures of rhazicine (200) and rhazimine (201), were first isolated. Further investigation of the extract of leaves of M. acutiflorus gave a new alkaloid, rhazicine Noxide (202) [56,67]. To our knowledge, the first report of the co-occurrence of monoterpenoid indoles meloyunine C (203) and precursor Δ14vincamenine (104) in same plant, supporting the biosynthesis of quinoline from M. yunnanensis and concurring with previous in vivo tracer experiments in the literature [53].

Extraction and isolation
Four methods were used for extraction and isolation. Firstly, the air-dried sample was extracted with EtOH or MeOH. The extract was partitioned between organic solvent and HCl solution. The acidic water-soluble materials, adjusted to pH 9 -10 with ammonia solution, were extracted with EtOAc, MeOH or CHCl 3 to give an alkaloidal extract. Then, the extract was subjected to silica gel column chromatography (CC), TLC, MPLC with RP-18 gel CC, Sephadex LH-20 CC [27][28][29]32,34]. Secondly, M. fusiformis were extracted exhaustively with EtOH. After concentration, the material was obtained which was then dissolved in citric acid or tartaric acid, filtered and the solution adjusted to pH 5 and 7 with NH 4 OH, and then extracted with CHCL 3 , repeatedly. The extract was subjected to silica gel column chromatography (CC). Lastly, some dried Melodinus spps were ground and extracted with acetone or EtOH. The extract was filtered and concentrated and the residue extracted with similarity principle. The extract was subjected to silica gel column chromatography (CC), Et 2 O, CHCL 3 and MeOH being used as eluents.

Cytotoxic activity
Continuous investigation of bioactive indole alkaloids from the genus Melodinus, include tests against seven human tumor cell lines, HL-60, SMMC-7721, A-549, MCF-7, SW480, SK-BR-3 and PANC-1.The results showed that these compounds exhibited stronger inhibitory activity with low IC 50 than that of cisplatin (Table 6).

Anti-inflammatory effects
Two new compounds 187-188 exhibited significant, dose-dependent inhibition of the production of lipopolysaccharide (LPS)-induced NO, IL-6 and IL-8 in mice macrophages. The results suggested that these new quinoline alkaloids could be new potential candidates for development as anti-inflammatory agents [46].

Other activities
11,19R-dihydroxytabersonine (30) had significant anti-fertility activity. The results of spermicidal effect in vitro showed that spermicidal concentration of 0.2 mg/ml [15]. Rhazinilam (204) evaluated against the disassembly of microtubules into tubulin with IC 50 value of 2 -3 μM [79,80]. Metabolism studies were conducted in order to investigate the reasons for the in vivo lack of activity of (-)-rhazinilam. The oxidative metabolism of (-)-rhazinilam were markedly less active than it in vitro, which might explain its in vivo inactivity [80].

CONCLUSION
Plants of the family Apocynaceae have been proven to be good sources of indole alkaloids, quinoline alkaloids, which originated from the condensation of tryptophan with secologanin. Some have been reported to display in vitro cytotoxicity against several human cancer cell lines, anti-inflammatory effects and antifertility activity. However, there still arise questions concerning the structure-activity relationships and elucidation of the action mechanism. There are 23 species of this genus whose isolation and activities have not previously been reported. Thus, much attention should be paid to the other Melodinus species via further phytochemical, pharmacological and structure-activity relationship studies.