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Natural Products-Sources of New Drugs

This Review article, 'Natural Products as Sources of New Drugs over the last 25 Years' (on-line 2/07,17pp) provides an analysis of the sources of new and approved drugs for the treatment of human diseases--from David Newman and Gordon Cragg at the Natural Products Branch, Developmental Therapeutics Program of the National Cancer Institute (NCI).
Their review covers all approved agents for all diseases worldwide over this time frame and from 1950 to 6/2006 for all approved antitumor drugs worldwide. They characterize a subdivision of drugs to describe "natural product mimics" ('NM') to join the original primary drug divisions.(1)
They present extensive data and technical analysis yet overall this Review is readable by the non- scientist-- their 'Discussion" section is very interesting.

From the data presented, the utility of natural products as sources of novel structures but not necessarily the final drug entity is still alive and well. In the area of cancer,over the time frame from around 1940s to date, of the 155 small molecules, 73% are other than "S" (synthetic), with 47% actually being either natural products or directly derived therefrom. ... Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have, in fact, been used in the opitimization of many recently approved agents, we are able to identify only one de novo combinatorial compound approved as a drug in this 25 year plus time frame.

...[T]he development of high throughput screening based on molecular targets had led to a demand for the generation of large libraries of compounds to satisfy the enormous capacity of these screens... [but] the shift away from large combinatorial libraries has continued, with the emphasis now being on small , focused collections that contain much of the 'structural aspects' of natural products. Various names have been given to this process, including "Diversity Oriented Syntheses" but we prefer to simply say 'more natural product-like' in [certain] terms.

...the developmental capability of combinatorial chemistry as a means for structural optimization once an active skeleton has been identified without par. The expected surge in productivity however has not materialized...thus, the number of new active substances (NASs), also known as New Chemical Entities (NCEs)...hit a 24-year low of 25 in 2004 with a rebound in 2005 to 54...

...Research being conducted is continuing the modification of active natural product skeletons as leads to novel agents, so in due course, the numbers of materials developed by linking Mother Nature to combinatorial synthetic techniques should increase. This aspect, plus the potential contributions from the utilization of genetic analysis of microbes, [is] discussed at the end of this review.

In the middle of 2006, the botanical preparation Hemoxin was approved in Nigeria following demonstration of efficacy in clinical trials as a treatment for sickle cell anemia. This is a mix of plants that came from native healer information and thus classified as 'true ethnobotanical preparation'.
To us, a multi-disciplinary approach to drug discovery, involving the truly novel molecular diversity from natural products sources, combined with total and molecular combinatorial synthetic methodologies, and including the manipulation of biosynthetic pathways, provides the best solutions to the current productivity crisis facing the scientific community engaged in drug discovery and development.

So it is no surprise that natural products, herbal remedies and the like are so much in the news and also a focus of regulatory agencies-- in most instances asking for the science behind their medicinal claims.
For scientists who study molecules, they find their subject in both natural and unnatural, organic and inorganic entities. The questions they ask know only the boundaries established by their current understanding of the phenomena they study.
Also, the recognition of the role natural products play in the current scientific trend is shaping in great part interactions/discussions by and among representatives of Eastern and Western countries who meet again and again in various international venues to share and protect their traditional knowledge and scientific prowess. Viewpoints continue to take shape in giving the various endeavors fair direction in setting mutual priorities and developing capablities.

(1)http://pubs.acs.org/cgi-bin/sample.cgi/jnprdf/asap/pdf/np068054v.pdf published in J. Nat. Prod. 2007, 70, 461-477, See below for a few helpful key terms for reference from 2000, 2003 chemistry textbooks.

Excerpted from certain references in text books, 2000, 2003:
‘Organic Chemistry’, Maitland Jones, Jr. , Princeton University, 2000 (Norton & Company),and
‘Chemistry & Chemical Reactivity’ Kotz & Treichel 5th Edition 2003 (Thomson Brooks /Cole).
Organic chemists ask questions about molecular structures, how reactions take place, look at the energy involved to make certain reactions happen, study details of how molecules come together to make other molecules .
Still other chemists focus on synthesis, the goal here is the construction of a target molecule from smaller, available molecules. Nature can make a certain molecule in an extraordinary competent way but Nature cannot make changes on request.
About key terms:
Atom(s): The smallest particle of an element that retains the chemical properties of that element; a neutral atom consists of a nucleus, or a core of protons and neutrons, orbited by number of electrons equal to the number of protons ..atoms are the building blocks of all matter, everything is made of atoms of different kinds in distinctive ways.
Molecule(s): The smallest units of a compound that retains the properties of that compound.
Molecular compound(s): A compound formed by the combination of atoms (and not ionic compounds).
Molecular formula: A written formula that expresses the number of atoms of each type within one molecule of a compound.
Molecular orbital: an orbital not restricted to the region of space surrounding an atom but extending over several atoms in a molecule. Molecular orbitals are formed though an overlap of atomic or molecular orbitals. Molecular orbitals can be bonding, nonbonding or antibonding.

Excerpted from Maitland’s Into:
Atom and molecules are really quite strange things, they are not like the objects that populate our daily experience. For one thing, molecular events take place on a time scale we cannot easily appreciate . under typical condition in a gas phases a single molecule undergoes from (10 to the 10th) to (10 to the 11th) collisions per second. Let's call one of those collisions an ordinary event in a molecule's 'life', analogous to an ordinary event in a human life--a heartbeat for example.
If your heart beats 60X a minute, you will experience more than 2.5 billion beats over an 80-year lifespan. So in one second a molecule undergoes more ordinary events than your heart will beat in your entire life. We do not appreciate such differences easily!
Organic chemistry is traditionally described as the chemistry of carbon-containing compounds. In the last century[1800s], it was thought that organic molecules were related in an immutable way to living things. The idea was that organic compounds could be made only from molecules derived from living things and gave rise to the notion of a vital force being present in carbon containing molecules. Despite the demise of the vital force idea, carbon -containing molecules certainly do have s strong connection to living things including ourselves. Indeed carbon provides the backbone for all the molecules that make up soft tissues of our bodies. Our ability to function as living sentient creatures depends on the properties of carbon-containing organic molecules ...

Maitland’s chapters focus on aspects of structure-the 3-dimensionality, in the detail of archtypical structures of organic chemistry. The discussion of structure and of 'difference' enables a discussion of several building -block reactions of organic chemistry--substitution and elimination, fundamental reactions among others.
Kotz & Triechel’s text moves from a discussion of the basic tools of chemistry to the structure of atoms and molecules, states of matter and the control of chemical reactions and ends with the chemistry of the elements.

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