Early In Vitro Cytotoxicity Testing of Diorganotin Carboxylates

When organotin halides are dissolved in water, the pH of the solution dramatically decreases because they are converted into organotin hydroxides that are afterwards possibly converted into insoluble bis(triorganotin) oxides or dior-ganotin oxides, thereby liberating protons. Di- or tri-organotin carboxylates do not suffer from this disadvantage as such derivatives, when dissolved in water, generally remain intact for long periods, i.e. days.

Reviews describing the anti-tumour properties of organotin compounds have been published recently28 30 and, therefore, only salient aspects of their anti-tumour potential will be discussed here.

The influence of the R and R' groups of R2Sn(OCOR')2 or {[R2Sn (OCOR')]2O}2 on cytotoxicity has been determined, allowing for the development of a structure-activity relationship.31 33 The di-«-butyltin compounds were among the more potent compounds examined. Di-ra-butyltin derivatives have found several industrial applications2 and, therefore, di-ra-butyltin oxide, a useful starting material to synthesize di-ra-butyltin derivatives, is commercially available and quite inexpensive.

The conversion of polymeric and insoluble (R2SnO)« into R2Sn(OCOR')2 or {[R2Sn(OCOR')]2O}2 is facile: (R2SnO)« and R'COOH are mixed in a mixture of ethanol and toluene, and heated. Very quickly, the heterogeneous reaction mixture becomes a clear solution. The water/toluene/ethanol azeotrope is then distilled off and, when the concentrated remaining solution is cooled down, sometimes, the reaction product precipitates directly from solution.

If the 1/«(R2SnO)/R'COOH molar ratio is 1:1, generally, dimeric distannox-anes {[R2Sn(OCOR')]2O}2 of type 1 are obtained (Figure 22.1):34 38

A 1:2 molar ratio generally yields diorganotin dihalides, R2Sn(OCOR')2, of type 2 (see Figure 22.1).39 53

Tin NMR spectroscopy can be used to easily distinguish between diorganotin derivatives of carboxylic acids of types 1 and 2: the tetraorganodicarboxylato-distannoxane dimers of type 1 are characterized by two tin resonances because they contain two heterotopic tin atoms, those forming the Sn2O2 four-membered

Figure 22.1 Chemical structures of tetraorganodicarboxylatodistannoxane dimers {[R2Sn(OCOR')]2O}2 (type 1) and diorganotin dicarboxylates R2Sn(OCOR')2 (type 2)

Figure 22.1 Chemical structures of tetraorganodicarboxylatodistannoxane dimers {[R2Sn(OCOR')]2O}2 (type 1) and diorganotin dicarboxylates R2Sn(OCOR')2 (type 2)

Table 22.2 Typical ID50 values (ng/ml) of di-n-butyltin dicarboxylates: di-n-butyl digibberellate and di-n-butyltin diterebate. The ID50 values of cisplatin and doxorubicin are given for comparison

R'COO

O HO"

CH3 O

Gibberellate

CH3 O

Gibberellate

R'COO

R'COO

Terebate

Terebate

Compound MCF-7 EVSA-T WIDR IGROV M19 MEL A498 H226

R' COO = gibberellate

2, R = Bu, 27 25 134 18 61 61 104 R' COO = terebate

CPT 699 422 967 169 558 2253 3269

DOX 10 8 11 60 16 90 199

ring and those that are substituents of that ring, whereas a single tin resonance characterizes the diorganotin dicarboxylates of type 2.

The ID50 values observed for typical diorganotin derivatives of carboxylic acids are given in Table 22.2. They show that di-n-butyltin digibberellate is a little more potent in vitro than cisplatin, but less active than doxorubicin, whereas di-n-butyltin diterebate is much more potent than cisplatin in vitro against all cell lines. Its potency is similar to that of the best clinical drug doxorubicin.

Several other series of organotin derivatives of carboxylic and dicarboxylic acids were routinely synthesized and tested (see for instance Ref. 54 56).

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