The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part I

Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen "Neglected Tropical Diseases" (NTDs) defined as such by WHO due to the neglect of financial investment into research and development of new drugs by a large part of pharmaceutical industry and neglect of public awareness in high income countries. Another major tropical protozoan disease is malaria (caused by various Plasmodium species), which -although not mentioned currently by the WHO as a neglected disease- still represents a major problem, especially to people living under poor circumstances in tropical countries. Malaria causes by far the highest number of deaths of all protozoan infections and is often (as in this review) included in the NTDs. The mentioned diseases threaten many millions of lives world-wide and they are mostly associated with poor socioeconomic and hygienic environment. Existing therapies suffer from various shortcomings, namely, a high degree of toxicity and unwanted effects, lack of availability and/or problematic application under the life conditions of affected populations. Development of new, safe and affordable drugs is therefore an urgent need. Nature has provided an innumerable number of drugs for the treatment of many serious diseases. Among the natural sources for new bioactive chemicals, plants are still predominant. Their secondary metabolism yields an immeasurable wealth of chemical structures which has been and will continue to be a source of new drugs, directly in their native form and after optimization by synthetic medicinal chemistry. The current review, published in two parts, attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs.

In vitro anti-proliferation/cytotoxic activity of epingaione and its derivatives on the human SH-SY5Y neuroblastoma and TE-671 sarcoma cells / Actividad citotóxica antiproliferativa in vitro de la epingaiona y sus derivados, sobre el neuroblastoma humano sh-sy5y y las células del sarcoma te-671

Epingaione (4-Methyl-1-(5-methyl-2, 3,4,5-tetrahydro-[2,3']bifuranyl-5-yl)-pentan-2-one) was isolated as one of the major lipophilic secondary metabolites from the leaves and stems of Bontia daphnoides L. The compound gave 79.24and 50.83anti-proliferation/cytotoxic activity on the human SH-SY5Y neuroblastoma and TE-671 sarcoma cells in vitro at 50 pg/mL, respectively. Epingaione was transformed into eleven derivatives under laboratory conditions using ethanol, some gave greater anti-proliferation/cytotoxic activity on the cancer cell lines tested. One of the derivatives (compound 2) with enhanced cytotoxic activity was elucidated as 5'-Ethoxy-5-methyl-5-(4-methyl-2-oxo-pentyl)-2,3,4,5-tetrahydro-5'H-[2,3']bifuranyl-2'-one. Both epingaione and compound 2 caused an accumulation of arrested or dead SH-SY5Y neuroblastoma in the m-phase of the cell cycle as revealed by the m-phase specific marker KE 67.

La epingaiona (4-Metil-1-(5-metil-2,3,4,5-tetrahidro-[2,3']bifuranil-5-il)-pentan-2-uno) fue aislada como uno de los principales metabolitos lipofilicos secundarios de las hojas y tallos de Bontia daphnoides L. El compuesto produjo 79.24 % y 50.83 % de actividad citotóxica/anti-proliferación sobre el neuroblastoma humano SH-SY5Y y las células del sarcoma TE-671 in vitro a 50 µg/mL, respectivamente. La epingaiona fue transformada en once derivados en condiciones de laboratorio, utilizando etanol. Algunos produjeron mayor actividad citotóxica y antiproliferativa sobre las líneas celulares cancerosas sometidas a ensayo. Uno de los derivados (compuesto 2) de elevada actividad citotóxica fue identificado como 5'-Etoxi-5-metil-5-(4-metil-2-oxo-pentil)-2,3,4,5-tetrahidro-5'H- [2,3']bifuranil-2'-uno. Tanto la epingaiona como el compuesto 22 causaron una acumulación de neuroblastomas SH-SY5Y muertos o detenidos en la fase m del ciclo celular, según lo revela el marcador KE 67 específico de la fase m.