Taxus brevifolia

Ben Merritt

-Biology, Chemistry, and Pharmacology

Taxus (Taxaceae)- Evergreen trees or shrubs; not resinous

or aromatic

Roots – fibrous, woody

Leaves – needles, persist for several years (evergreen), spirally arranged

(alternate), resin canals may be present or absent

Bark – scaly or fissured

-6-10 species --- mostly unique

because of geographical

location

Taxus Growth Forms

T. chinensis

T. bacata“Repandens”

T. bacata“Little Gem”

T. brevifolia var. reptaneta

Taxus

Seeds – one per “cone,” surrounded by fleshy aril Pollen Cones – produced annually,

axillary, globose/ovoid

- Reproductive Structures

Seed Cones – 1-2 ovules, axillary

T. cuspidata

- Aril is edible but seeds are toxic

T. brevifolia Anatomy-shrub/small

tree 15-25m tall (200y to mature)

-dioecious

-bark scaly; outer scales

purplish/brown

-branches horizontal/droo

ping

-vegetative reproduction

common

-inner scales reddish/purple

-leaves 1-2cm x 1-4mm

-epidermal cells mostly taller

than wide

-seeds mature late

summer/fall

Habitat

-Western NA – Alaska south to Montana, Idaho and

California- Lives in moist

areas around river banks, ravines

-Sea-level to 2200m

-May grow in sun or shade

(needs acclimation

period)

Common Names

The only common names seem to be “Pacific Yew” and

“Western Yew.” - “yōl’-kō” in

Concow language (CA)

Latin Name

Taxus brevifolia (Nutt.)

brevi - = short, abbreviated

-folia = foliage; leaves

↵1. Loanword of Scythian (Iranian) origin; means simply “yew” in Latin

2. From the Greek, meaning “bow”; origin of word “toxic”

Traditional Uses

-Was sometimes used in Native American

(Algonquin) smoking mixtures called

kinnikinnick

-Needles of Taxus with uva-ursi plant said to

produce “too strong of an effect”

-Wood was used by Native

American tribes to make bows

-Used similarly by the ancient

Greeks/Romans –

considered toxic

Modern Uses

-Originally found to have cytotoxic effects on cancer cells (antineoplastic) -Less toxic than other species, most taxol Used on a variety of

cancers (breast, ovarian, lung, colon, leukemia)

-Often 24-h infusion every few weeks

Parts used

Primarily the bark and leaves (active

constituents in phloem)

-Was initially tested against KB cells (HeLa

derivatives); have carcinoma and

papilloma cancersOrder of potency (extract)

stem > bark > root > needles > wood >twigs

-Needles first require non-polar wash to

remove fats (then CO2, or other)

T. cuspidata

Constituents

- Taxol – Isolated first in 1966 by Wall and Wani (0.02%, dried bark)

Contains variety of Taxanes –

taxol most active

Mechanism of Action

Microtubule (MT) stabilization

-Beta-tubulin binding only

-Promotes assembly, discourages depolymerization

-Prevents mitosis, eventual cell death

Undesirable Effects of Taxol Administration

(Long-term)

Causes build-up of MT’s

Effects rapidly-dividing cells – gut, bone marrow, lymphocytes

-Hypersensitivity (allergic reaction)

-Mostly due to vehicle (cremophor) – some use albumin -Peripheral Neuropathy (doses greater than 170mg/m2) – also may result from cremophor

-Neutropaenia

-Problems with heart (arrythmia, bradycardia)

-Vomiting-Mucositis (dig., painful)-Dysphagia

Isolation/SynthesisFrom the bark (0.01-0.02%):

MeOH, then methylene chloride/H20 (or chloroform)

From the needles (0.025-0.044%):

Hexane pre-wash (waxes, lipids)

- [ ] in bark rises over summer- Concentration increases in plant material after letting sit for a week or two

Hauser Chemical used 15,000lb of bark for 1kg of taxol (0.015%)

Semi-synthetic route (80%)

10-deacetlybaccatin IIITotal synthesis

possible

Other Methods of Isolation

Plant Cell Fermentation: Grow Taxus calluses in aqueous media, extract taxol (chromatography, crystallization)-Bristol-Myers Squibb

Endophytic Fungi?-Taxomyces andreanae

Original study – (1993)-15-20% of taxanes is taxol-24-50ng/liter-May require precursors

Later study – (2013)-Not found to have homologous genes/evidence of trans-kingdom gene transfer

- Thought to remain in membrane after isolation from tree!!!

The Future

Taxol and related taxanes are useful in the treatment of cancer, but they have many terrible side effects.

Further research should be centered around:

1. Molecules with less toxic effects2. Specific cell targeting (work is being done with IG)3. Better vehicles for administration (albumin, pro-drug)

• ATCC. “KB (ATCC® CCL-17TM).” <http://www.atcc.org/products/all/CCL-17.aspx> May 1 2014.  • EPA. “Greener Synthetic Pathways Award: Bristol-Myers Squibb Company.”

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