Natural Product Chemistry as a Source for Anti-Cancer AgentsDelaney Cheek, Levi Gates, Alex Harlan, Anne Hwang

Objective● Overview the history of natural products and role in chemotherapy● Identify the drug discovery process for chemotherapeutic agents● Review current naturally derived chemotherapeutic agents in development● Determine the value of using natural products in chemotherapy

The earliest recorded use of natural products...● From Mesoptamia (2600 BC)

○ Oils of■ Cedrus species (cedar)■ Cupressus sempervirens (cypress)■ Glycyrrhiza glabra (licorice)■ Commiphora species (myrrh)■ Papaver somniferum (poppy juice)

● Most likely had been used long before recorded use○ ie/ Evidence of use in Egypt in 2900 BC

● Egypt had the largest record of over 700 drugs from natural sources (mostly plants) and used honey as the main vehicle

Medicinal plants- Majority of knowledge pertaining to natural product use is derived from humans

experimenting by trial and error on themselves using medicinal plants- Palatability trials resulted in many untimely deaths in the search for food and

disease treatments

Other sourcesFungus

Penicillium notatum → you guessed it, penicillin!

Puptoporus betulinus → steamed to produce charcoal (antiseptic)

Agaricus campestris Linnaeux → soothe cancer of the throat

Lichen → used as dyes majorly, used as raw materials for medicines

Usnea dillenius → used for scalp in old times. Still in dandruff shampoos

Algea → used in drinks for sore throats & chest infections

Historically Important Natural Products Acetylsalicylic acid → derived from salicin, which came from the bark of a particular willow tree.

Papaver somniferum L. → resulted in isolation of alkaloid products like morphine (1803).

Digitalis Purpurea L. (foxglove) → contains digitoxin which increases cardiac conduction

Why Nature? - The significance of natural product chemistry

● Mother nature is a great chemist○ Nature has had millions of years to come up with many compounds with varying properties○ Produced as part of a chemical defense system to protect the producing organism from attack○ Molecular structures and functionalities of natural products are beyond human ideas

https://www.scripps.edu/shen/NPLI/whynaturalproducts.html

Research Methods● Reviewed literature found via Web of Science, PubMed, Google Scholar, and

Embase.● Search terms including: “natural products”, “chemotherapy”, “cytotoxicity”,

“anti neoplastic agent” and “nature”.● Investigated NCI website to define the steps of natural product development.● Interviewed natural product researchers at the University of Iowa who are

developing anti cancer drugs.● Contacted to Barry R. O’Keefe, Chief of Natural Products Branch of DTP by

E-mail

New Drugs from 1981 to 2014

Figure 1. All new approved drugs 1981−2014; n = 1562. Figure 2. All anticancer drugs 1981−2014; n = 174.

*Natural products include natural products per se, derivatives, pharmacophore, or mimics of natural products

Source: Newman DJ, Cragg GM. Natural Products as Sources of New Drugs from 1981 to 2014. J Nat Prod. 2016.

Discovery: Anti-cancer DrugsThe plant: roughly 70%

Vincristine (VCR), etoposide, paclitaxel (Taxol ),

docetaxel, topotecan, and irinotecan

The marine organisms: ~5%

Cytarabine and Nucleoside Analogues,

Trabectedin, Halichondrin B and Eribulin

Bacteria and Fungi:

Rapamycins, Carfilzomib, Midostaurin

Mayer Am, et al. The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends Pharmacol Sci. 2010 Jun.Cragg GM, Pezzuto Jm. Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents. Med Princ Pract. 2016.

Overview of NCI · Part of the National Institutes of Health (NIH)

· Federal government’s principal agency for cancer research and training

· The largest funder of cancer research in the world

· Provide education publication through PDQ(physician data query) and drug information of cancer

· Coordination and support of all phases of clinical trials across 2,500 clinical trial sites

· Cancer research for prevention, detection, diagnosis, and survivorship

· Drug discovery and development through developmental therapeutics program (DTP)

Source: www.cancer.gov

Cancer Drug Screening via NCI DTP

NCI-60 Human Cell Lines Screen:

* 60 different human tumor cell lines: breast, ovary, prostate, colon, lung, kidney, brain, leukemia, and melanoma

* Identification of novel compounds with growth inhibition and killing of tumor cell lines

DTP selects structures for screening

Send sample to NCI Repository, 10 -15 mg

NCI–60 cell lines screens sample and enters results in database

Extensive testing in animals before testing in human (antitumor efficacy and selectivity)

DTP reposits sample and assigns NSC number

When a compound shows anticancer activity

Source: www.cancer.gov/research/areas/treatment

Clinical testing

Ke Hu, Xinsheng Yao. Methyl protogracillin (NSC-698792): the spectrum of cytotoxicity against 60 human cancer cell lines in the National Cancer Institute's anticancer drug screen panel. Anti-Cancer Drugs 2001 Jul;12(6):541-7.

Anticancer Development Strategies - Early Stages

Schwartsmann, G., Winograd, B., & Pinedo, H. M. (1988). The Main Steps in Development of Anticancer Agents, 12, 301–313.

NCI Experimental Therapeutics Program

https://next.cancer.gov/about/default.htm

Drug Development Process1. Pre-Clinical

a. Acquisitionb. Screeningc. Production/Formulationd. Toxicology Evaluation

2. Clinicala. Phase I Studiesb. Phase II Studiesc. Phase III Studies

Schwartsmann, G., Winograd, B., & Pinedo, H. M. (1988). The Main Steps in Development of Anticancer Agents, 12, 301–313.

Drugs in Development - OSW1 ● Natural product from the roots of Ornithogalum saundersiae found in Japan● Dr. Jin from the University of Iowa College of Pharmacy● Primary MOA: reduce / Inhibit GRP78 (folding of proteins)

○ growth○ survival ○ Immune escape & spread

1. Tang, Yuping, et al. “Structure, Bioactivity, and Chemical Synthesis of OSW-1 and Other Steroidal Glycosides in the Genus Ornithogalum.” Chemical Reviews, vol. 113, no. 7, 2013, pp. 5480–5514., doi:10.1021/cr300072s.

1. Tang, Yuping, et al. “Structure, Bioactivity, and Chemical Synthesis of OSW-1 and Other Steroidal Glycosides in the Genus Ornithogalum.” Chemical Reviews, vol. 113, no. 7, 2013, pp. 5480–5514., doi:10.1021/cr300072s.

Drugs in Development - ZJ1● An analog of OSW-1

○ Simplified chemical structure○ Same potency & selectivity○ Easier to synthesize

● Currently marketed as payload for antibody-drug conjugates for cancer therapy● The University of Iowa is one of the only places to produce this drug currently ● Have several very interested companies who are using ZJ1 in preclinical

research

Currently Used Chemotherapeutic Agents

Source: clinicaltrials.com & cancer.gov

Natural agents

Origin of source

Treatment MOA Clinical trials

Paclitaxel Pacific yew tree Taxus brevifolia

Breast, Non-small cell lung, Ovarian

Binds to tubulin and inhibits the disassembly of microtubules

2987

Etoposide mandrake root Podophyllum peltatum

Small cell lung, Testicular cancer

Acts primarily in the G2 and S phases of the cell cycle

1383

Vinblastine The plant Catharanthus roseus

Breast, Kaposi sarcoma, Non- Hodgkin and Hodgkinlymphoma,

Disrupts microtubule formation during mitosis Interferes with glutamic acid metabolism

464

Topotecan(Cisplatin)

Asian tree Camptotheca acuminata

Cervical,Ovarian, Small cell lung cancer

Stabilizes topoisomerase I-DNA covalent complexes, inhibiting religation of topoisomerase I

381

Conclusion● Future implications:

a. There’s value in natural product research

i. Natural products will always be applicable to new discoveries

● Recommended sources for additional reading:

a. Natural Products as Sources of New Drugs from 1981 to 2014: https://pubs.acs.org/doi/10.1021/acs.jnatprod.5b01055#

b. Main Steps in Development of Anticancer Agents: https://www.sciencedirect.com/science/article/pii/0167814088900205

c. Currently in development: Schweinfurthin https://ir.uiowa.edu/cgi/viewcontent.cgi?article=7480&context=etd

References1. Mayer Am, et al. The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends Pharmacol Sci. 2010

Jun;31(6):255-65.

2. Cragg GM, Pezzuto Jm. Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents. Med Princ Pract. 2016;25 Suppl 2:41-59.

3. Alejandro M.S. Mayer et al. The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends pharmacol Sci. 2010 Jun;31(6):255-65.

4. Newman DJ, Cragg GM. Natural Products as Sources of New Drugs from 1981 to 2014. J Nat Prod. 2016 Mar 25; 79(3):629-61.

5. Ke Hu, Xinsheng Yao. Methyl protogracillin (NSC-698792): the spectrum of cytotoxicity against 60 human cancer cell lines in the National Cancer Institute's anticancer drug screen panel. Anti-Cancer Drugs 2001 Jul;12(6):541-7.

6. Schwartsmann, G., Winograd, B., & Pinedo, H. M. (1988). The Main Steps in Development of Anticancer Agents, 12, 301–313.