NAS Ukraine
Department 2

chemistry of complex compounds

Novel coordination compounds of platinum metals with phosphonic acids.

The compounds of platinum metals have always been a matter of interest to scientists in view of physicochemical properties characteristic of them and their use, in recent years as drugs in medicine as well, since they show antitumor, antimicrobial and antiviral properties.
However, their use, primarily of platinum-based compounds, is limited by high nephrotoxicity, hematologic toxicity and neurotoxicity.
In recent years, report of lower toxicity of palladium-, rhodium- and ruthenium-based compounds in comparison with analogous platinum-based compounds have appeared, which makes it possible to develop in prospect new drugs based just on these metals.
The known compounds of platinum, including cisplatin and carboplatin, which are used now in medical practice, contain, in addition to platinum, counter-ions or neutral molecules, chemically bonded to it, which undoubtedly affect the physicochemical properties of the compound as a whole and are responsible for both favorable and adverse consequences of its use.
Therefore, when organizing this work, we aimed our efforts at synthesizing novel compounds based on palladium, rhodium and ruthenium, in which they are chemically bonded to phosphonic acid derivatives, and investigating their properties.
Why just with phosphonic acid derivatives? Analysis of literature data shows that individual phosphonic acids exhibit properties, thanks to the specific character of phosphonic groups, which enable them to be used in biology and medicine as radiopharmaceuticals for the treatment of bone diseases and malignant tumor. Compounds with direct carbon-phosphorus bond (C-P) are part of phosphonolipids, phosphonoglycanes, phosphonoproteins of cell membranes. Lipids containing aminophosphonic compounds are resistant to enzymatic hydrolysis and ensure stability and normal operation of external cell membranes.
Diphosphonic acids are derivatives of pyrophosphate, a constituent of bone tissues, but are characterized, in contrast to it, by the presence of a (P-C-P) fragment of structure, which enables their bonding to the bone matrix. At the same time, the side chains of molecules are responsible for their antiresorptive properties.
In view of the ability of diphosphonic acids to form stable complex compounds with metal ions, they are used in the treatment of diseases caused by the derangement of calcium metabolism, inhibit the crystallization of calcium salts in soft tissues, etc. Diphosphonic acids also show anti-inflammatory, antibacterial, antiviral and, above all, antitumor properties. An especially valuable feature is that they act quickly and are at the same time nontoxic and stable for a long time.
Hydroxyethylenediphosphonic (HEDP) and nitrilotrimethylphosphonic (NTMP) acids are most widely used in medicine. Both HEDP acid and its disodium salt (etidronate) are used as calcium metabolism regulators and in the treatment of Paget’s disease. HEDP acid increase calcium incorporation into bone tissue, prevents the development of osteoporosis, suppresses the formation and growth of calcium oxalate salts in kidneys. According to the data we have, HEDP acid is recommended in the USA for use as a pharmaceutical for the treatment of patients with metastasized bone cancer.
NTMP acid, as HEDP acid, is characterized by affinity for bone tissues; therefore it is part of drugs for the treatment of bone cancer and serves as a "transport agent" which delivers radionuclides to the site of pathology.
Basing on the said above, we set us a task of combining chemically in the composition of one compound two components, each of which is characterized by anticancer activity. On the one hand, it is a cytostatic, palladium, rhodium or ruthenium ion, which is less toxic than platinum ion, and on the other hand derivatives of phosphonic acids.
The latter are also characterized by anticancer activity; they are almost nontoxic, but the chief thing is that being pyrophosphoric acid derivatives, they are characterized by affinity for bone tissues and accumulate in bone tissues by a mechanism acting in the living organism, ensuring drug delivery to the target. Thus, delivery exactly to the target and goal-directed action of drug are presumed.
Such a drug can combine a high antineoplastic action of all its constituents, a low toxicity, stability of action during a long time and, above all, goal-directed action, which is due to the properties of its chemically bonded constituents which have the property of accumulation in bone tissues.
What have we done to date? Procedures for the synthesis and purification of a number of derivatives of phosphonic acids, e.g. hydroxyethylenediphosphonic, nitrilotrimethylphosphonic, aminoethylidenediphosphonic, aminoisobutyldiphosphonic and N,N-dimethylaminomethyldiphosphonic acids, have been mastered and updated in some cases.
On the basis of generalization of literature data, a scheme of synthesis of a number of novels amino-, hydroxyl-containing and other derivatives of mono-, di-, tri-, tetraphosphonic acids, which are not described in literature, has been drawn up. Methods for the synthesis of a number of novel complex compounds of palladium and rhodium with HEDP, NTMP and other acids, which are not described in literature, have been developed; these compounds have been synthesized, and their physicochemical properties have been investigated. Conclusions about their structure have been drawn.

The main thing is that together with colleagues from the R.Ye. Kavetskii Institute of Experimental Pathology, Oncology and Radiobiology of the Ukrainian NAS (department headed by Academician V.F. Chekhun), anticancer activity of the palladium compounds synthesized towards a number of cancer diseases has been established.
The compounds being investigated by us are comparable in anticancer activity (effect of action) to cisplatin , but are half as nephrotoxic and much cheaper than cisplatin ([Pt(NH3)2Cl2]). It has been proved that palladium is present in the animal bone tissue, indicating indirectly that the therapeutic effect is due to the introduction o just our compound into the animal organism since there is no palladium in living organisms. At the same time, no changes in the size and weight of animal organs have been observed, which were noted when cisplatin was used. At the samеtime, no canges in the size weight of animal organs have been observed, which were noted when cisplatin was used. The chief thing is that phosphonic acid chemically bonded to palladium has performed "transport function": has delivered the cytostatic agent to the right address – to the affected bone.

Cytotoxic activity against primary-culture cells of Ehrlich’s carcinoma of mice.

System under investigation IC50, mg/ml
(NH3)2PtCl2 0.023
K2[PdCl4] with HEDP 0.028

Cytotoxic activity against primary-culture cells of lymphatic leukemia L1210.

System under investigation IC50, mg/ml
(NH3)2PtCl2 0.016
K2[PdCl4] with HEDP 0.025


System under investigation Content of urea, mmol/l
(NH3)2PtCl2 9.7±0.5
K2[PdCl4] with HEDP 5.0±0.3

Our plan:
To increase the volume of works on the synthesis and investigation of new compounds of platinum metals, gold and perhaps silver on the basis of known phosphonic acid derivatives and new ones to be synthesized by a synthesized by us and to increase accordingly to volume of works on biochemical testing and investigation (R.Ye. Kavetskii Institute of Experimental Pathology, Oncology and Radiobiology of Ukrainian NAS) for the possible creation of novel drugs.

Key researchers:
Candidates of Chemical Sciences Kozachkova Oleksandra M., Tsaryk Nataliya V. and Korobko Sergiy V., applications-engineer Dudko Anatolii V., post-graduate student Rudenko Volodymyr L.
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