Natural Products That Changed Society

Abstract

Until the end of the 19th century all drugs were natural products or minerals. During the 19th century chemists succeeded in isolating pure natural products such as quinine, morphine, codeine and other compounds with beneficial effects. Pure compounds enabled accurate dosing to achieve serum levels within the pharmacological window and reproducible clinical effects. During the 20th and the 21st century synthetic compounds became the major source of drugs. In spite of the impressive results achieved within the art of synthetic chemistry, natural products or modified natural products still constitute almost half of drugs used for treatment of cancer and diseases like malaria, onchocerciasis and lymphatic filariasis caused by parasites. A turning point in the fight against the devastating burden of malaria was obtained in the 17th century by the discovery that bark from trees belonging to the genus Cinchona could be used for treatment with varying success. However isolation and use of the active principle, quinine, in 1820, afforded a breakthrough in the treatment. In the 20th century the synthetic drug chloroquine severely reduced the burden of malaria. However, resistance made this drug obsolete. Subsequently artemisinin isolated from traditional Chinese medicine turned out to be an efficient antimalarial drug overcoming the problem of chloroquine resistance for a while. The use of synthetic analogues such as chloroquine or semisynthetic drugs such as artemether or artesunate further improved the possibilities for healing malaria. Onchocerciasis (river blindness) made life in large parts of Africa and South America miserable. The discovery of the healing effects of the macrocyclic lactone ivermectin enabled control and partly elimination of the disease by annual mass distribution of the drug. Also in the case of ivermectin improved semisynthetic derivatives have found their way into the clinic. Ivermectin also is an efficient drug for treatment of lymphatic filariasis. The serendipitous discovery of the ability of the spindle toxins to control the growth of fast proliferating cancer cells armed physicians with a new efficient tool for treatment of some cancer diseases. These possibilities have been elaborated through preparation of semisynthetic analogues. Today vincristine and vinblastine and semisynthetic analogues are powerful weapons against cancer diseases.

Keywords: artemisinin; cancer; chloroquine; ivermectin; malaria; moxidectin; onchocerciasis; quinine; vinblastine; vincristine.

Scheme 1

Formation of acetic acid from carbon, chlorine and sulfur.

Figure 1

Acetylsalicylic acid (6) and phenazone (7).

Scheme 2

Simplified presentation of the photosynthesis [25].

Figure 2

Life cycle of Plasmodium parasites: When an infected female Anopheles mosquito takes a blood meal approximately eight to 10 sporozoites are introduced into the blood. Either the sporozoites have entered hepatocytes after 45 min. or they are cleared. In the liver the sporozoites proliferate asexually for between 5 days (P. falciparum) and 15 days (P. malariae). A proportion of hepatic schizonts may rest in the liver as hyonozoites in the case of P. ovale and P. vivax infections. The hypnozoites may awake weeks or months after the infection. The merozoites delivered to the blood invade erythrocytes, feed on the proteins mainly hemoglobin and proliferate asexually. After 36 hours (P. malariae, P. ovales, P. vivax and P. knowlesi) or 54 hours (P. malariae) the cells rupture and release between 6 and 36 merozoites, which invade healthy erythrocytes. The characteristic fever attacks appear when the erythrocytes rupture. After a series of asexual proliferation gametocytes appear. Gametocytes are ingested during a blood meal of an Anopheles mosquito, in which they undergo a sexual proliferation [7].

Figure 3

(A): World map 1660. A large part of South America was colonized by Spain (light green) and Portugal.(Green) Russia is dark blue (B): World map 1754. Almost all South America is colonized British colored red, whereas only tiny parts of Africa. (C): World map 1822. Even though Australia was known since 1606 it was not colonized until James Cook described the continent in 1770. (D): World map 1898. The major part of Africa is colonized and by 1914 all of Africa was colonized (Russia black, German and Belgium colonies blakc, Turkish colonies Light green , British colonies red, France colonies dark blue, Dutch colonies light red (comons.wikimedia.org/wiki/File:World_1898_empires_colonies_territory.png, Accessed 1 April 2021 )

Figure 4

Cinchona officinalis L. and C. pubescens Vahl. [38].

Figure 5

Examples of Cinchona barks stored at The Museum of Natural Medicine & The Pharmacognostic Collection (University of Copenhagen).

Figure 6

Major Cinchona alkaloids. Quinine and quinidine are included on WHO list of essential medicines (https://www.who.int/medicines/publications/essentialmedicines/en/ine, accessed on 1 April 2021).

Figure 7

Early synthetic antimalarial drugs. Chloroquine and primaquine are included on WHO list of essential medicines (https://www.who.int/medicines/publications/essentialmedicines/en/ine, accessed on 1 April 2021).

Figure 8

Antimalarial drugs. Except for tetracycline all the compounds are synthetic drugs. Proguanil, sulfadoxime, lumefanthrine and tetracycline are included in WHO list of essential medicines (https://www.who.int/medicines/publications/essentialmedicines/en/, accessed on 1 April 2021).

Figure 9

Ferroquine (26).

Figure 10

Digestion of hemoglobin (27) to give ferroprotoporphyrin (28), which spontaneously oxidizes to ferriprotoporphyrin IX (29). Precipitation of hemozoin (30) prevents the toxic effects of 29 [76,77].

Figure 11

Artemisia annua. (http://www.plantsoftheworldonline.org/taxon/urn:lsid:ipni.org:names:304416-2, accessed on 1 April 2021).

Scheme 3

Conversion of artemisinin to clinical used artemisinins: artemether (33), arteether (34) and artesunate (35) [80,81]. Artesunate and artemether are included in WHO list of essential medicines (https://www.who.int/medicines/publications/essentialmedicines/en/, accessed on 1 April 2021).

Scheme 4

The iron(II) ion of ferroprotoporphyrin (27) activates artemisinin (31) to give a reactive C-radical (36), which might alkylate ferroporotporphyrin (27) preventing precipitation [84]. The exact mechanism of alkylation, C-radial formation and the possibility of degradation of other biomolecules are still debated [77].

Figure 12

Synthetic antimalarial drugs. Mefloquine and amodiaquine are included in WHO list of essential medicines. (https://www.who.int/medicines/publications/essentialmedicines/en/, accessed on 1 April 2021).

Figure 13

Recent antimalarial drugs expected to overcome resistance among mutated parasites.

Figure 14

Life cycle of Onchocerca volvus. The patient is infected by a blood meal from a blackfly belonging to the genus Similium. The nematode (worm) is situated in nodules in the skin. The male nematode is up to 5 cm and the female nematode up to 70 cm long. The female worms produce a number of microfilariae, which cause the symptoms [88,89]. Like in the case of malaria transmission is performed by an insect.

Figure 15

Avermectins and ivermectin [90]. The glycoside side chain is attached to C-13.

Figure 16

Macrolactone endectocides [97].

Figure 17

Moxidectin (53) [102].

Figure 18

Catharanthus roseus (The Museum of Natural Medicine & The Pharmacognostic Collection, University of Copenhagen).

Figure 19

Vinblastine (54) and vincristine (55) are native natural products, whereas vindesine (56), vinorelbine (57) and vinflunine (58) are semisynthetic analogues [11].

Scheme 5

Dimerization of indolalkaloids to give vincaalkaloids. For details see [22].

Figure 20

Cell division. In the prometaphase the nuclear envelope breaks down and the chromosomes condense and microtubules contact chromosomes at the kinetochores. In the early metaphase most chromosome have congressed to the equator. In the anaphase, depicted in Figure 20, the duplicated chromosomes have separated and move toward the spindle pools and the cell divides to form two daughter cells. In the telophase the separated chromosomes have reached the spindle poles and the cells divides into daughter cells [114]. The vinca alkaloids destroy the mitotic spindle and consequently block the mitosis [113,114].