A natural product is a chemical compound or substance produced by a living organism-found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design. This product can be considered as such even if it can be prepared by total synthesis. And it is usually secondary metabolite. Secondary metabolite has functions that are not directly involved in the growth, development or reproduction of the organism. It is generally produced as a defense mechanism against predators or to aid the organism adapting to its surrounding environment. Natural products could be extracted from tissues of terrestrial plants, marine organisms or microorganism fermentation broths. A crude (untreated) extract from any one of these sources typically contains novel, structurally diverse chemical compounds.
Table 1 Brief information of the five FDA-approved natural products
|Product name||Main source||Indication||Approved date|
|Spinosad||Saccharopolyspora spinosa||Head lice infestations||2011.01|
|Ingenol mebutate||Euphorbia peplus||Actinic keratosis||2012.01|
|Omacetaxine mepesuccinate||Cephalotaxus harringtonii||Chronic myeloid leukemia||2012.10|
There are many drugs have been discovered and developed from natural products in the past, such as lovastatin, reserpine, artemisinin and so on. And natural products and their derivatives occupy a high proportion in the field of new drugs discovery. According to the several reports, five natural products have been approved by FDA since 2011 (Table 1). Omacetaxine mepesuccinate and trabectedin, for example, have been approved as orphan drugs by FDA in 2012. Most of the natural products are small molecular. So FDA-approved new natural products (derivatives not included) are approved by FDA is a challenging mission. Obviously, one of the reasons is that not all natural products can be fully synthesized. Besides, many natural products have very complex structures that are too difficult and expensive to synthesize on an industrial scale. Such compounds can only be harvested from their natural source—a process which can be tedious, time consuming, and expensive, as well as being potentially unsustainable for the resource. Furthermore, the number of structural analogues that can be obtained from harvesting is severely limited.
Below is detailed information for the five natural products:
Spinosad (trade name Natroba), the active ingredient, is derived from the fermentation of a soil actinomycete bacterium, Saccharopolyspora spinosa. Spinosad is a mixture of spinosyn A and spinosyn D in a ratio of approximately 5 to 1 (spinosyn A to spinosyn D). Natrobe Topical Suspension is indicated for the topical treatment of head lice infestations in patients four years of age and older. It causes neuronal excitation in insects. After periods of hyperexcitation, lice become paralyzed and die.
Ingenol mebutate (trade name Picato) is a substance found in the sap of the plant Euphorbia peplusand an inducer of cell death. Picato gel is indicated for the topical treatment of actinic keratosis. For treatment of actinic keratosis on the face and scalp Picato gel, 0.015% should be applied to the affected area once daily for 3 consecutive days. For treatment of actinic keratosis on the truck and extremities Picato gel, 0.05% should be applied to the affected area once daily for 2 consecutive days.
Omacetaxine mepesuccinate (trade name Synribo) is a natural product first discovered in cephalotaxus harringtonii. Now it was prepared by a hemi-synthetic process from cephalotaxine, an extract from the leaves of Cephalotaxus sp. Synribo is indicated for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI). The mechanism of action of omacetaxine mepesuccinate has not been fully elucidated but includes inhibition of protein synthesis and is independent of direct Bcr-Abl binding. Omacetaxine mepesuccinate binds to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit from a strain of archaeabacteria. In vitro, omacetaxine mepesuccinate reduced protein levels of the Bcr-Abl oncoprotein and Mcl-1, an anti-apoptotic Bcl-2 family member. Omacetaxine mepesuccinate showed activity in mouse models of wild-type and T315I mutated Bcr-Abl CML.
Crofelemer (trade name Fulyzaq), a botanical drug substance that is derived from the red latex of Croton lechleri Müll. Arg. It is an oligomeric proanthocyanidin mixture primarily composed of (+)-catechin, (-)-epicatechin, (+)-gallocatechin, and (-)-epigallocatechin monomer units linked in random sequence. Fulyzaq is an anti-diarrheal indicated for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on anti-retroviral therapy.
Trabectedin (trade name Yondelis) is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove. Adduct formation triggers a cascade of events that can affect the subsequent activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death. Yondelis is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.
Lahlou, Mouhssen. "The success of natural products in drug discovery." Pharmacology & Pharmacy 4.3A (2013): 17.
Karlsdóttir, Ásrún. "The origin of FDA approved natural product new chemical entities." (2016).