With the development of scientific and technological means, there are many ways to obtain drugs, including separation from plants and other natural sources, synthetic chemistry, combinatorial chemistry and molecular modeling. Although pharmaceutical companies have found a variety of ways to find drugs in recent years, natural products, especially medicinal plants, are still an important source of new chemical entity (NCES) drugs. From 2015 to 2016, about 1/4 of the world’s best-selling drugs came from natural products and their derivatives. Natural products play an important role in the treatment of many diseases, including cancer, AIDS, Alzheimer’s disease, malaria and pain. Below, we mainly introduce the representative drugs from natural products in the above-mentioned diseases.
Some examples of drugs derived from natural products
Arteether is an effective antimalarial drug which has been listed in the United States. It is a sesquiterpene lactone isolated from artemisinin. Other artemisinin derivatives are at different stages of use or clinical trials as anti-malarial drugs in Europe. It is well known that the discovery and use of artemisinin and its derivatives against malaria is a strong color in China and the world. Artemisinin and its derivatives are listed in China, such as dihydroartemisinin, artemisinin piperaquine and so on.
Galantamine is a natural product that has been listed in the United States. In Russia in the early 1950s, Galantamine was approved for the treatment of Alzheimer’s disease. It slows down the process of neurodegeneration by inhibiting acetylcholinesterase (AChE) and binding and regulating nicotine acetylcholine receptor (NACHR). Galanthamine derivatives have also been listed in China, such as galanthamine hydrobromide, dihydrogalanthamine hydrobromide and so on.
On June 15, 2016, Sobi (Swedish Orphan Biovitrum AB) announced that the Food and Drug Administration (FDA) has approved Orfadin for the treatment of hereditary typhinemia type I (HT-1). Nitisinon was modified by plant toxin leptospermone. Its pharmacological effect is to inhibit 4-hydroxyphenylpyruvate dehydrogenase (4-hppd). The inhibition of 4-hppd enzyme can prevent tyrosine catabolism and the accumulation of toxic biological products in liver and kidney.
Tiotropium has been listed in markets for the treatment of chronic obstructive pulmonary disease (COPD). Tiotropium bromide is an inhaled anticholinergic bronchodilator based on ipratropium bromide modification. Tiotropium bromide showed increased efficacy and more lasting effects than other effective COPD drugs.
Morphine-6-glucuronide is a metabolite of morphine from Papaver somniferum L, a plant of the poppy family. Morphine-6-glucuronide is now in the research and development stage of phase III clinical research and development, in order to replace morphine, as a painkiller with fewer side effects. Morphine derivatives are important painkillers in the domestic and foreign markets, and there are more related derivatives in China.
Vinflunine, a modification of vinblastine extracted from Catharanthus roseus, was developed by, Pierre Fabre and launched in 2009 under the trade name Javlor ®. The cytotoxicity of vinblastine is achieved by binding to tubulin. They have common binding sites on tubulin dimer, which can inhibit the synthesis of microtubule polymerization and hinder the formation of pituitary microtubule, so as to stop the metaphase of mitosis and prevent the division and proliferation of cancer cells. Compared with four kinds of vinblastine antineoplastic drugs: vincristine, vindesine and vinorelbin, Vinflunine showed less neurotoxicity in clinical trials.
Calanolide A entered the research and development stage of clinical II stage at the highest level. It is a natural product of dipyricoumarin, which was isolated from Photinia mandshurica in Malaysia. Calanolide A is an anti-HIV drug, which is used as a non-nucleoside reverse transcriptase inhibitor of HIV-1 (NNRTIs). The mechanism of action and cross-resistance of different structures of NNRTIs may be very different, and NNRTIs may still have a strong inhibitory effect on NRTIs (nucleotides inhibitor, nucleoside reverse transcriptase inhibitors)-resistant mutants. Compared with NRTIs, NNRTIs often has many advantages in terms of safety and bioavailability. Therefore, Calanolide A is likely to have a good market prospect.
Natural products play an important role in the preparation of new chemical entity (NCE). In 2002-2012, about 28 percent of NCE was natural products or derived from them. Research related to natural products accounted for about 48 percent of the reported NCE in 2002-2012. In addition, known natural products may have new biological activities. Since the emergence of human genome sequencing, thousands of new molecular targets have been confirmed. With the emergence of high-throughput screening, compounds from natural products are expected to show potential activity. Many compounds have been isolated from traditional medicinal plants and have been verified to act as molecular targets, such as indirubin, can selectively inhibit cyclic dependent kinase. Cucurbitacin I, which is highly selective in inhibiting the JAK/Stat3 pathway in activated Stat3 tumors, selectively kills cancer cells on normal cells by activating p38. Therefore, natural products are a treasure trove of concern and have great potential for drug acquisition.
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