Natural Products and Biologics
While many small molecule drugs have been developed using rational drug design and organic synthesis, other drug classes exist, such as natural products and biologics.

Natural Products
The term “natural product” broadly refers to a compound that is isolated from a living organism, (e.g., marine organisms, plants or bacteria).⁵⁷ Natural products may or may not be biologically active but the term is often used to refer to biologically active entities or commercial products. Natural products encompass compounds of varying molecular weight, from those that fit in the small molecule category (MW <700) to large molecules (MW 700-2000) and to complex mixtures of large molecular weight (MW >2000). For example, salicylic acid, the active ingredient in aspirin, was isolated from willow bark⁵⁸ (MW 138). Other examples that range from small to larger MW include:

• nicotine (MW 162)
• hinokitiol (MW 164)
• quisqualic acid (MW 189)
• caffeine (MW 194)
• cantharidin (MW 196)
• kainic acid (MW 213)
• resveratrol (MW 228)
• indirubin (MW 262)
• anisomycin (MW 265)
• atropine (MW 289)
• retinoic acid (MW 300)
• cocaine (MW 303)
• quinine (MW 324)
• penicillin G (MW 334)
• camptothecin (MW 348)
• xanthohumol (MW 354)
• lactacystin (MW 376)
• colchicine (MW 399)
• wortmannin (MW 428)
• betulinic acid (MW 456)
• emetine (MW 480)
• epoxomicin (MW 554)
• herbimycin (MW 574)
• bafilomycin A1 (MW 622)
• veratridine (MW 673)
• nigericin (MW 724)
• FK-506 (MW 804)
• okadaic acid (MW 805)
• vinblastine (MW 810)
• aclacyinomicin A (MW 811)
• rapamycin (MW 914)
• actinomycin (MW 1255)
• valinomycin (MW 1111), and
• vancomycin^59,60( MW 1449)

Large molecules such as the peptide gramicidin D⁶¹ (MW 1882), the protein hirudin⁶² (MW 6979) and complex mixtures of polymeric glycans like heparin^63,64(MW 12,000-15,000) are also products isolated from naturally occurring sources.

Natural products have been used in medicine for thousands of years and have provided the basis for modern drug discovery.^65,66,67 Because the availability of the natural source may be limited, commercially available natural products such as paclitaxel are often prepared on a large scale by chemical synthesis^68,69 or produced by genetically engineered bacterial or plant cell sources.^70,71

Biologics
The term “biologic” may encompass natural products or newly invented products.  Biologics are usually peptides, proteins (e.g., insulin, hirudin, or monoclonal antibodies), and complex mixtures of large molecules (e.g., heparin). Biologics are usually large molecules (> 1000 MW) and are not made by chemical synthesis. Rather, they are extracted from animal blood or tissue, harvested from genetically modified cell culture, or isolated from plant matter.⁷²

Natural Products and Biologics in the Treatment of Cancer
Oncology research has produced both small molecule and biologic anti-cancer products. Many natural products have been the basis for small molecule treatments for cancer. Some include:

• Anthracyclines (e.g., daunomycin, (also called daunorubicin), doxorubicin, epirubicin)
• Quinones (e.g., mitomycin C)
• Polyketides such(e.g., calicheamycin, epothilone B)
• Plant-derived agents (e.g., vinblastine, paclitaxel, etoposide)⁷³

Small molecule agents that are not natural products, and that were invented through rational drug design, include the tyrosine kinase inhibitors (e.g., erlotinib and imatinib)⁷⁴ and FGFR (fibroblast growth factor receptor inhibitors) such as dovitinib.⁷⁵

Anti-cancer biologics include monoclonal antibodies like bevacizumab and rituximab, biological response modifiers like BCG live, immunomodulators such as bortezomib and interferon-α2b and the growth-hormone inhibitor octreotide.⁷⁶ Immunotheraputics vs. the Programmed death (PD-1) receptor are also very promising.⁷⁷

Brain-penetrant Natural Products
Because most biologics are large molecules, they do not cross the blood-brain barrier easily. Therefore, small molecule natural and synthetic products have been the most applicable to brain-targeted therapeutics.  Morphine, quisqualic acid, cannabis, forskolin, reserpine, kainic acid, cocaine, ephedrine, pseudoephedrine, and cathinone are all examples of natural products that have significant neurological effects. These compounds serve as tools to help us understand the mechanisms of the brain.⁷⁸ For example, forskolin is often used to increase the levels of cAMP in cell physiology experiments.⁷⁹ Mesembrenone and mesembrine (serotonin re-uptake inhibitors and PDE4 inhibitors), and kavain (mechanism currently unknown) are three natural products that have shown some efficacy in treating depression.⁸⁰

Biologics comprise a growing proportion of marketed drugs, both in number and in sales. Table 1 illustrates growth of biologics relative to small molecules.

Table 1.  New Molecular Entity (NME) Count and Sales of Biologics and Small Molecules

Summary
In summary, natural products and biologics differ from small molecules based on their origin, and molecular weight, respectively. Natural products may have a small molecular weight, but are derived from plant or animal material. Many well-known therapeutics including aspirin and penicillin were derived from living organisms. Biologics typically have higher molecular weight, are peptides, and do not readily pass the blood-brain barrier. Though sales and development of biologics has increased in recent years, because of their size, biologics have limited therapeutic value in disease areas requiring blood-brain barrier penetration.