Thiophene Rings

Thiophene rings comprise another functionality that is easily activated to elec-trophilic species. Thiophene itself is metabolized to the S-oxide, which is viewed as the key primary reactive intermediate. Nucleophilic groups such as thiols react at position 2 of the thiophene S-oxide via a Michael-type addition [23]. Tielinic acid (Figure 8.23) is oxidized to an S-oxide metabolite [24], creating two electron-withdrawing substituents on C2 and a resultant strongly electrophilic carbon at C5 of the thiophene ring [24]. This highly reactive metabolite covalently binds to the enzyme metabolizing it (CYP2C9), triggering an autoimmune reaction resulting in hepatitis. Rotation of the thiophene ring leads to a compound in which the sulphoxide is less reactive and [24] can create a less reactive sulphoxide metabolite which reacts primarily at C2 with nucleophiles. This metabolite is stable enough to escape the enzyme and alkylate other proteins leading to direct toxicity.

Fig. 8.23 Structure of tienilic acid (A) and an isomeric variant (B) which cause hepatotoxicity by autoimmune and direct mechanisms respectively, following conversion to sulphoxide metabolites and resultant electrophilic carbon atoms.

The thiophene ring has also been incorporated into a number of drugs which have diverse toxicities associated with them (Figure 8.24). Ticlopidine, a platelet function inhibitor, is associated with agranulocytosis in patients [25]. Suprofen, a non-

Fig. 8.23 Structure of tienilic acid (A) and an isomeric variant (B) which cause hepatotoxicity by autoimmune and direct mechanisms respectively, following conversion to sulphoxide metabolites and resultant electrophilic carbon atoms.

O CI

O CI

O CI

"n

COOH

Suprofen

COOH

Fig. 8.24 Structures of

suprofen and ticlopidine, compounds containing a thiophene ring and associated with diverse toxicities in patients.

Fig. 8.24 Structures of

Suprofen

Ticlopidine steroidal anti-inflammatory agent has been withdrawn from the market due to acute renal injury [26].

The association of ticlopidine with agranulocytosis has been further investigated [27]. A general hypothesis for white blood cell toxicity is the activation of the drug to a reactive metabolite by HOCl, the principal oxidant being generated by activated neutrophils and monocytes (as in Section 8.4). Under these types of oxidation conditions ticlodipine is activated to a thiophene-S-chloride (Figure 8.25) which reacts further to form other products including a glutathione conjugate.

Fig. 8.25 Metabolism of ticlopidine by white blood cells to the reactive thiophene-S-chloride (A) and further breakdown products of this reactive metabolite.

Tenidap (Figure 8.26) is a dual cyclooxygenase (COX) and 5-lipoxygenase (5-LPO) inhibitor developed as an anti-inflammatory agent. Severe abnormalities in hepatic function were reported in Japanese clinical trials [28]. Although the thiophene is not directly implicated in these findings, the ready activation of this system to potential reactive metabolites may be suggestive of the involvement of this function.

Fig. 8.25 Metabolism of ticlopidine by white blood cells to the reactive thiophene-S-chloride (A) and further breakdown products of this reactive metabolite.

Fig. 8.26 Structure of tenidap, a compound containing a thiophene ring and associated with changes in hepatic function.

114 | 8 Toxicity 8.8

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Cure Tennis Elbow Without Surgery

Cure Tennis Elbow Without Surgery

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