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ARTICLES: Jana Kaspárková, Olga Nováková, Oldrich Vrána, Francesco Intini, Giovanni Natile, and Viktor Brabec Molecular Aspects of Antitumor Effects of a New Platinum(IV) Drug Mol Pharmacol 2006; 70: 1708-1719 [Abstract] [Full text] [PDF]

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Method of preparation and identity of compounds tested

Frantisek Zak   (9 January 2007)

Author Response to Zak letter

Viktor Brabec   (9 January 2007)

Method of preparation and identity of compounds tested 9 January 2007
Frantisek Zak, researcher PLIVA-Lachema, Brno, Czech Republic Send letter to journal: Re: Method of preparation and identity of compounds tested zak{at}lachema.cz Frantisek Zak	To the Editor, I have worked in the field of platinum anticancer drugs for long time. The article by Kasparkova, et al. , “Molecular Aspects of Antitumor Effects of a New Platinum(IV) Drug,” shows the results of research with platinum complexes adamplatin(II) and adamplatin(IV). According to citations in this article, these compounds are identical to compounds LA-9, CAS No.[250613-98-0] and LA-12, CAS No. [250611-20-2], developed by our team in PLIVA - Lachema a.s., Brno, Czech Republic. Unfortunately, I believe that the "Materials and Methods" probably describes the synthesis and characterization of different compounds. During the preparation of adamplatin(II) by the method described in the article, ion, and not coordination, compounds of adamantylamine and platinum are created or a mixture of both. The type of compounds developed by this procedure depends on many parameters that are not sufficiently described in the article. For preparation of adamplatin(IV) from adamplatin(II), two synthetic steps are necessary. However, this is described only as a citation to Giandomenico et al. Inorg. Chem. 34, 1015 (1995). This article does not describe complexes of platinum with adamantylamine, so the process was probably modified, but no modification is mentioned. Preparation of Pt complexes with adamantylamine (LA-9 and LA-12) was first described in patents (WO99/61450, WO99/61451) and in the article [Zak et al.; J.Med. Chem. 47, 761 (2004)]. The characterization of the identity of the prepared compounds is inadequate to determine which compounds were prepared and subsequently tested. Incomplete results of elemental analysie are shown (content of Pt and Cl is missing). Only 1H NMR spectra are described and in the case of IR spectrometry, only Pt-Cl bound is evaluated, which corresponds to many types of platinum complexes. The summary formula of adamplatin(IV) - C14H26Cl3KN2Pt neither corresponds to LA-12 nor to the structural formula, shown in the article. Due to the lack of information about the exact method of preparation and the incomplete results of identification, we have some misgivings about the identity of the compounds used for biological tests. It would be helpful to provide this information which is necessary to the elucidation of the structure of compounds in the article. Frantisek Zak PLIVA-Lachema, Brno, Czech Republic
Author Response to Zak letter 9 January 2007
Viktor Brabec Send letter to journal: Re: Author Response to Zak letter brabec{at}ibp.cz Viktor Brabec	Response to the letter of F. Zak containing his comments to the paper Kasparkova, J., Novakova, O., Vrana, O., Intini, F., Natile, G. and Brabec, V. (2006) Molecular aspects of antitumor effects of a new platinum(IV) drug. Mol Pharmacol, 70, 1708-1719. In the following text we summarize our disposition of the Zak’s comments. Zak mentions in the version of his letter which we had available that “I work in the field of platinum anticancer drugs for long time. In this article, are shown results of research with platinum complexes adamplatin(II) and adamplatin(IV). According to citations in this article, these compounds are identical with compounds LA-9, CAS No. [250613-98-0] and LA-12, CAS No. [250611-20-2], developed by our team in PLIVA-Lachema a.s., Brno, Czech Republic. Unfortunately, in "Materials and Methods" is probably described synthesis and characterisation of different compounds.“ Zak mentiones that he works in the field of platinum drugs for a long time. However, we found in the database “Web of Science” that he published only 5 papers in the field of platinum antitumor drugs and the first appeared in 2004. On the other hand, for instance the corresponding author (Viktor Brabec) has published in the field of platinum drugs about 130 papers in international refereed journals and the first appeared in 1983. Prof. Giovanni Natile from University of Bari, co-author of the above- mentioned paper, who synthesized the compounds adamplatin(II) and adamplatin(IV), has the competence in the synthesis, characterization, stereochemistry, and reactivity of platinum compounds documented by almost 200 papers published in international refereed journals since 1980. His competence and achievements in the field of platinum chemistry have been also appreciated by electing him the president of the European Association for Chemical and Molecular Sciences (former Federation of European Chemical Societies). We do not understand why Zak mentions that adamplatin(II) and adamplatin(IV) are identical to those synthesized by them earlier. This information is given in the paper and few references related to this fact are also included. On the other hand, the idea of platinum compounds containing the adamantylamine ligands was described first by other authors (e.g. Inorg. Chem. 32 (1993) 2717-2723) and not by Zak at al. in 2004. And finally we do not agree with his view that synthesis and characterization of different compounds is described in our paper. The reasons are contained below in the letter written by professor Natile: The statement of professor Giovanni Natile: I am a bit surprised by the letter sent by F. Zak and I will briefly answer his questions in the same order. “Preparation of platinum(II) species”. The procedure used by us is very general and in fact similar to that used by F. Zak (and briefly described in his paper in J. Med. Chem. 2004, 47, 761-763), i.e. the reaction of trichlorido(ammine)platinum(II) anion with adamantylamine. The only differences between our procedure and that of Zak concern the counter cation (which does not take part in the reaction) and the solvent. “Preparation of platinum(IV) species”. In our case, as in the case of Zak ( J. Med. Chem. 2004, 47, 761-763), the platinum(IV) species was obtained from the platinum(II) species by oxidation with hydrogen peroxide followed by the treatment with acetic anhydride. Also this latter procedure is very general and was used by many other authors before Zak. This is the reason why we only quoted the paper of Giandomenico et al. (Inorg. Chem. 1995, 34, 1015) and did not give any detailed description of the preparation procedure. In addition, the journal Molecular Pharmacology as well as our article is not focused to details of chemical synthesis so that the synthesis of the compounds was described in the extent usual for the articles published in Molecular Pharmacology. “Characterization of the compounds”. Since the prepared compounds are not new and have already been reported in the literature, which is obvious from the article, we have given in our paper only the analytical and spectroscopic data which are, according to our opinion, necessary and sufficient to prove the identity of the compounds. A final comment of Zak concerns the elemental analysis given for the platinum(IV) species. It is clearly indicated in our paper (and I am surprised that Zak has overlooked the chemical formula following the elemental composition C14H26Cl3KN2Pt) that the analyzed sample of the platinum(IV) species contained one mole of crystallized KCl per mole of the complex. In the specific preparation (not described in detail) the starting platinum(II) species already contained a cocrystallized KCl which was found also in the crystallized final platinum(IV) species. The presence of cocrystallized KCl cannot affect the type of investigations we had planned and therefore we did not proceed to its separation. In addition, Zak wrote in his letter that the analysis was incomplete, however over 99% of papers reporting elemental analysis give figures only for C, H, and N (and sulphur when present), the reason being that these are the elements which are analyzed by standard elemental analysis equipments (in fact it can be clearly seen in the Zak’s paper in J. Med. Chem. 2004 that Pt was not analyzed). In conclusion, we believe that we have provided a sufficient information and explanation of our view that the compounds used in our work were characterized in a sufficient way. Thus, we strongly reject any doubts of their identity raised by Zak. January 3, 2007 Viktor Brabec