Description
Topotecan was launched in the US for the second-line treatment of ovarian
cancer. It can be prepared in four steps from camptothecin and is a water soluble
derivative of the natural product with decreased toxicity. Unlike its chemical relative
irinotecan, topotecacan in not a prodrug and does not require bioactivation. It is an
inhibitor of topoisomerase I. Specifically, it inhibits the release of topoisomerase I
from DNA, where it relaxes supercoiled DNA, giving rise to single-strand breaks.
When the replication fork reaches this complex, double-stand breaks can occur. This
signals apoptosis and eventually gives rise to cell death. Evidence indicates
hycamtin is safe for people with impaired hepatic function.
Chemical Properties
Off-white Cryst
Originator
SmithKline Beecham (UK)
Definition
ChEBI: A pyranoindolizinoquinoline used as an antineoplastic agent. It is a derivative of camptothecin and works by binding to the topoisomerase I-DNA complex and preventing religation of these 328 single strand breaks.
Manufacturing Process
Camptothecin (CPT) - a compound isolated from the bark, leaves and fruit of
Camptotheca acuminate (Wall M. E. et al., J. Am. Chem. Soc. 88, 3888,
1966).
10-Hydroxycamptothecin (10-HCPT) was prepared by subjecting CPT (3.2 g
0.0092 mol), 0.8 g of Pt0 (prepared by pre-reduction of 8 g of amorphous
PtO2 in 80 ml of acetic acid for 1.5 h under 1 atm hydrogen pressure) and
acetic acid to 1 atm of H2 for 8.5 h after which theoretical amount of H2
absorbed (slightly more than 0.4 L) and uptake of H2 gets slowed down. The
reaction mixture was degassed under steam of helium and filtered through
celite and washed with acetic acid (20 ml). The resulting solution was treated
immediately with Pb(OAc)4 (6.4 g 0.014 mol) in portions and reaction
mixture, stirred vigorously under helium for 30 min. Gumy residue was
obtained on evaporation of solvent which was triturated with cold water (100
ml) to produce light brown solid. The solid was collected, washed with cold
water and air dried overnight when a mixture of 10-HCPT (44%), acetyl 10-
hydroxycamptothecin (10-AcHCPT, 26%) and unreacted CPT (32%) on HPLC
basis was obtained. This crude mixture was combined with 150 ml of 50%
acetic acid and heated under reflux conditions overnight. The reaction mixture
was cooled, concentrated to 20 ml and treated with cold water (100 ml) to
produce precipitate, which is filtered, washed with more cold water and dried
to afford 2.1 g of solid containing 10-HCPT (70%), 10-AcCPT (1.2%) and CPT
(21.3%) on the basis HPLC. Mixture was triturating with 0.5% aq HCl to
dissolve the water-soluble. When insoluble CPT was removed by filtration.
Water-soluble was extracted with chloroform and crystallized from boiling
solution of 20% of MeOH in CHCl3 by adding EtOAC dropwise until turbidity
appeared to obtain pure yellow 10-(HCPT), melting point 268°-270°C.
10-HCPT (0.364 g 0.01 mmol) and 40% aqueous dimethylamine (12 ml) was
added in dichloromethane (50 ml) in which anhydrous potassium carbonate
(2.17 g, 15 mmol) has been suspended. The reaction mixture was stirred at
room temperature for 5 h, then filtered and solid extracted with ethylacetate
(20 ml). The solvent is evaporated in vacuo giving a residue. The residue was
triturated with 0.5% aq HCl (50 ml) to dissolve the water-soluble adduct.
Water-soluble were partitioned with petroleum ether (3 times 50 ml) and
followed by ethylacetate (3 times 50 ml). The aqueous layer was lyophilized
as an off white hydrochloride salt of 9-[(dimethylamino)methyl]10-
hydroxy(20S)-camptothecin (topotecan hydrochloride) yield 0.236 g (65%).
Therapeutic Function
Antineoplastic
reaction suitability
reagent type: derivatization reagent
reaction type: Alkylations
Biochem/physiol Actions
Topotecan is a topoisomerase I inhibitor and an apoptosis inducer. It is a potent antineoplastic agent.
Clinical Use
Antineoplastic agent:
Treatment of metastatic ovarian, cervical and small cell lung cancer
Drug interactions
Potentially hazardous interactions with other drugs
None knownccccc
Metabolism
Topotecan undergoes reversible, pH-dependent hydrolysis of the active lactone moiety to the inactive hydroxyacid (carboxylate) form. A relatively small amount of topotecan is metabolised by hepatic microsomal enzymes to an active metabolite, N-demethyltopotecan; the clinical significance of this metabolite is not known. Excretion is via biliary and renal routes with 20-60
% excreted in the urine as topotecan or the open ring form.
storage
Store at -20°C,protect from light
References
[1] creemers gj1, lund b, verweij j. topoisomerase i inhibitors: topotecan and irenotecan. cancer treat rev. 1994 jan;20(1):73-96.
