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The role of aziridinyl cyclophosphazenes and related compounds as anticancer agents. A tentative quantum mechanical approach
Journal of Molecular Structure, 88 (1982) 317-324 THEOCHEM Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
THE ROLE OF AZIRIDINYL CYCLOPHOSPHAZENES AND RELATED COMPOUNDS AS ANTICANCER AGENTS. A TENTATIVE QUANTUM MECHANICAL APPROACH
GUY GUERCH, JEAN-PAUL FAUCHER, and JEAN-FRANCOIS LABARRE*
MARCEL GRAFFEUIL,
GASTON LEVY
Laboratoire Structure et Vie, Universite' Paul Sabatier, 118 Route de Narbonne, Toulouse Cedex (France)
31062
(Received 28 September 1981)
ABSTRACT The electronic structures of the various conformations and allotropic species of two promising anticancer drugs, namely MYKO 63 and SOAz, have been calculated using the CNDO/P approximation. The results allow prediction of the acidity (in the Lewis sense) of the aziridinyl-bearing atoms of the drugs which corresponds to the optimum anticancer activity possible upon coordination to DNA, as the Lewis-base target. INTRODUCTION
The interest in inorganic ring systems as anticancer drugs, initiated by Cemov et al. [l] in 1959, was recently revived by the discovery of the effectiveness of some aziridinocyclophosphazenes, N3P3Azd(MYKO 63) and N4P4AzS(MYKO 83) [ 2-41, and of some aziridinocyclodiphosphathiazenes (NPAz,),(NSOX) (SOF, X = F; SOPHi, X = Ph; SOAz, X = AZ) [ 5,6] on a wide variety of animal tumors, i.e. P388 chronic leukemia, L1210 acute leukemia, subcutaneous B16 melanoma, ependymoblastoma, osteosarcomas, line 26 colon carcinoma, Lewis Lung carcinoma, P815 Mastocytoma, line 26 mammary carcinoma, lymphomas, lymphosarcomas and Yoshida sarcoma. The most efficient drugs were in each case MYKO 63 and SOAz and so we attempted to elucidate the targets of their wide activity. Assuming DNA to be on,e such target, we first investigated the nature and intensity of the interactions in vitro between MYKO 63 or SOAz and DNA by the Scatchard technique using ethidium bromide as a probe [ 71. Thus it was found that MYKO 63 and SOAz do interact with DNA but we were unable to determine at what sites on DNA MYKO 63 and SOAz interact. However, the nature of these sites could be discriminated by Raman spectroscopy: MYKO 63 was found to interact in vitro essentially as a dialkylating agent on N7 and NH2 sites of adenine [8] whereas SOAz would interact *To whom any correspondence 0166-1280/82/0000-0000/$02.75
should be addressed. o 1982 Elsevier Scientific Publishing Company
318
preferentially, in the manner of an intercalating drug, on some specific oxygen atoms of the DNA ribose-phosphate backbone [ 91. Both types of interactions proceed through the following pathway: aziridinyl rings generate electrophilic carbocations which bind themselves to the nucleophilic sites of DNA mentioned above. Thus, assuming this mechanism to be the right one, it was considered possible to undertake a quantitative study on this basis of electronic structures and charge distributions in the ground state of MYKO 63, SOAz and related compounds. This report deals with the calculation of these electronic structures by the SCF-LCAO-MO technique within the CNDO/B approximation of Pople and Beveridge [lo] which has been widely used previously for similar investigations [ 111 . MOLECULAR
STRUCTURES
AND COMPUTATIONAL
DETAILS
Calculations were performed on the whole set (minus one, see below) of X-ray molecular structures which had been observed both for MYKO 63 and SOAz under various conditions. When MYKO 63 is crystallized from CC14,the single crystal belongs to the space group C2/c and the structure corresponds to the complex N3P,Az,*3CC14 [ 121. The geometry of the N3P3Azgmoiety is depicted in Fig. 1. When MYKO 63 is crystallized from C6H6, however, the situation is quite different (space group Rz, 2N3P3Az6C6H6) and the molecular structure of N3P,Az, contained here differs noticeably (Fig. 2) from the previous one, essentially as regards the relative conformations of the aziridinyl wings [ 13, 141. Calculations could not be performed, however, owing to the uncertainty of the locations of the H atoms in the MYKO 63 molecule. A quite distinct structure is, yet again, observed when MYKO 63 is crystallized from CS? (space group P212121) or from m-xylene (space group P2/c), the two actual mblecular structures of N3P3Azgbeing strictly identical however (Fig. 3) [15].
Fig. 1. Charge densities and Wiberg indices in MYKO 63 when recrystallized
from Ccl,.
319
Fig. 2. Molecular pattern of MYKO 63 when recrystallized from C,H,.
Two allotropes exist for SOAz [16] : SOAz 1; m.p. = 83°C [ 171, space group P212121, Z = 4 (Fig. 4) and SOAz 2; m.p. = 105°C [ 171, space group P21/c, 2 = 8, with two sets of crystallographically independent molecules, namely SOAz 2A and SOAz 2B (Figs. 5 and 6). The geometry of thiotepa, SPAz3, was described by Subramanian and Trotter [ 181 (space group P2Jc, 2 = 4) (Fig. 7). Electronic charges were computed using Mulliken’s population analysis and bond orders are those by Wiberg’s definition [ 191. ELECTRONIC STRUCTURES
Charge densities and Wiberg indices are collected in Figs. 1 and 3-7. The electronic structures of the five ring systems illustrate the classical Dewar’s islands model [20] in a similar way to that previously described for other cyclophosphazenes, cyclophosphathiazenes and derivatives [ 21-261. Table 1 lists some relevant charges of interest, namely the average values on the nitrogen atoms of the AZ groups linked to P (Q1), the nitrogen atom
Fig. 3. Charge densities and Wiberg indices in MYKO 63 when recrystallized from mxylene (or CS,).
320
Fig. 4. Charge densities and Wiberg indices in SOAz 1 (m.p. = 83°C).
of the AZ group linked to S (Q?) and on the P endocyclic atoms (Q3). It can be seen that Q1 and Qz remain constant throughout the series whereas Q3 increases from 4.64 f 0.01 for the five inorganic ring structures to 4.81 in thiotepa. Hence, the phosphorus atoms in MYKO 63 and SOAz are much more acid (acidity being measured by the lack of electrons in the molecular structure) than those in thiotepa. ELECTRONIC STRUCTURE AND ANTICANCER
ACTIVITY
A critical survey of the various modes of action of anticancer drugs with proteins, enzymes and nucleic acids (DNA, RNA) shows the presence of a common Lewis acid-base mechanism [ 271. In other words, the effectiveness of both the so-called “dialkylating and/or intercalating versus DNA” anticancer agents and of the carcinogenic chemicals depends on their ability to generate acidic (i.e. electrophilic) moieties which inhibit DNA replication by linking to DNA basic (i.e. nucleophilic) sites. Thus, the activity of any anticancer agent may be described by a coordination chemistry process involving the coordination of a Lewis acid drug on a Lewis base (i.e. DNA, assuming this to be the target) [28].
Fig. 5. Charge densities and Wiberg indices in SOAz 2A.
321
Fig. 6. Charge densities and Wiberg indices in SOAz 2B.
This novel account of mechanisms for anticancer effectiveness allows a tentative explanation of MYKO and SOAz anticancer properties to be proposed: these molecules both comply with the two following necessary conditions for optimal anticancer activity. (i) The molecular structure contains a backbone (N3P3 or NJPzS inorganic ring) stable enough relative to metabolisation to transport the drug to the target [29]. (ii) The molecular structure contains five or six ligands (aziridinyl “wings”) which can provide, in vivo, suitable electrophilic carbocations for coordination to nucleophilic sites of DNA through inter- and/or intra-cross-linkings [ 30-321. Moreover, the charge densities on the endocyclic AZ-bearing phosphorus and sulfur atoms of these drugs confer to these atoms an optimal acidity for anticancer activity when compared to other AZ-bearing drugs, i.e. thiotepa. MYKO and SOAz are more effective on any animal tumor than thiotepa and such an enhancement of activity can be reasonably related, in terms of electronic structure, to the higher acidic character of P (Q_r = 4.65) in MYKO and SOAz versus that in thiotepa (Qr = 4.81). In other words, anticancer activity depends on a convenient acidity of AZ-bearing P atoms which is maximal for an electron deficiency of about 0.35. This assumption is supported by the fact that the bis(aziridiny1) derivative of Rosenberg’s c&platinum (Fig. 8) exibits only poor antitumor properties. The structure of this Pt derivative shows that aziridinyl ligands are bonded to the platinum by way of their nitrogen lone pairs [33] and thus that these AZ
Fig. 7. Charge densities and Wiberg indices in thiotepa.
322 TABLE 1 Average charges onN(Az) linked to P(Q,), onN(Az)linked
to S (9,)
and on Patoms (Q,)
Drug
Q,
Q,
Q,
MYKO 63 (from Ccl,) MYKO 63 (from xylene) SOAz 1 SOAz 2A SOAz 2B Thiotepa
5.18 5.18 5.17 5.18 5.17 5.16
5.16 5.14 5.15 -
4.65 4.64 4.63 4.63 4.63 4.81
wings cannot be opened in vivo to provide carbocations, such a mechanism requiring the availability of the N lone pairs. Hence the poor anticancer effectiveness of (AzH),PtC12 is due to the lability of chlorines in the cis configuration in the same way as in c&platinum itself, the AZ wings playing no part. The question now arises as to why aziridine substitutes the two NH3 ligands of &-platinum (DDP) rather than the chlorine atoms through HCl elimination. An answer is provided on the basis of the DDP electronic structure as calculated recently by Barber et al. [34] using Slater’s SCF-Xol method [ 351. This structure shows that the charge density on platinum is 77.0025, conferring on this atom a very acid character (the electron deficiency = 0.9975). In this case, the Pt carrier is so acidic that the bonding of aziridine occurs preferentially through a coordination process involving N lone pairs rather than through a covalent Cl/Az substitution. Hence, (AzI-D2PtC12 does not fulfil the two conditions necessary for anticancer activity mentioned above as a consequence of the over acidic nature of the Pt backbone.
r”\
NH
Cl
Fig. 8. Molecular structure of (AzH),PtCI,.
323 CONCLUSION
It is possible to estimate that an electron deficiency of ca. 0.35 on Azbearing atoms corresponds to the highest antitumoral activity observed. As soon as the acidity of such atoms deviates from this value, either to higher or lower values, anticancer effectiveness decreases. Quantum calculations on new potential anticancer molecules are now in progress in order to support our assumption [ 361. If it is correct, then quantum mechanics could provide a time and cost effective method of screening new drugs with perhaps better anticancer activity even than MYKO and SOAz. REFERENCES 1 V. A. Cernov, V. B. Litkina, S. I. Sergievskaya, A. A. Kropacheva, V. A. Pershina and L. E. Sventaitkaya, Farmakol. Toksikol. (Moscow), 22 (1959) 365. 2 J.-F. Labarre, S. Cros, J.-P. Faucher, G. Francois, G. Levy, C. Paoletti and F. Sournies, Proceedings of the 2nd International Symposium on Inorganic Ring Systems (IRIS), Gottingen, Gesellschaft Deutsches Chemiker, 1978, p. 44. 3 J-F. Labarre, J-P. Faucher, G. Levy, F. Sournies, S. Cros and G. Francois, Eur. J. Cancer, 15 (1979) 637. 4 EORTC results from B. W. Fox (Manchester) and F. Spreafico (Milano) (1980). 5 J-F. Labarre, F. Sournies, J. C.Van de Grampel and A. A. Van der Huixen, ANVAR French Patent No. 79-17336, July 4, 1979; world extension July 4, 1980. 6 J-F. Labarre, F. Sournies, S. Cros, G. Francois, J. C. Van de Grampel and A. A. Van der Huizen, Cancer Lett., 12 (1981) 245. 7 J-L. Butour, J-F. Labarre and F. Sournies, J. Mol. Struct., 65 (1980) 51. 8 M. Manfait, A. J. P. Alix, J-L. Butour, J-F. Labarre and F. Sournies, J. Mol. Struct., 71 (1981) 39. 9 M. Manfait and J-F. Labarre, Adv. Mol. Relax. Interact. Processes, 21(1981) 117. 10 J. A. Pople and D. L. Beveridge, Approximate Molecular Orbital Theory, McGraw-Hill, New York, 1970. 11 J-F. Labarre, Struct. Bonding (Berlin), 35 (1978) 1 and references therein. 12 J. Galy, R. Enjalbert and J-F. Labarre, Acta Crystallogr., Sect. B, 36 (1980) 392. 13 T. S. Cameron, C. Chan, J-F. Labarre and M. Graffeuil, Z. Naturforsch., Teil B, 35 (1980) 784. 14 T. S. Cameron, M. Graffeuil and J.-F. Labarre, Acta Crystahogr., Sect. B, 38 (1982) 168. 15 T. S. Cameron, J. C. Van de Grampel, A. A. Van der Huixen and J-F. Labarre, Acta Crystahogr., Sect. B, 38 (1982) in press. 16 J. Galy, R. Enjalbert, A. A. Van der Huizen, J. C. Van de Grampel and J-F. Labarre, Acta Crystallogr., Sect. B, 37 (1981) 2205. 17 J. C. Van de Grampel, A. A. Van der H&en, A. P. Jekel, D. Wiedijk, J.-F. Labarre and F. Sournies, Inorg. Chim. Acta, 53 (1981) L169. 18 E. Subramanian and J. Trotter, J. Chem. Sot. A, (1969) 2309. 19 K. A. Wiberg, Tetrahedron, 24 (1968) 1083. 20 M. J. S. Dewar, E. A. C. Lucken and M. A. Whitehead, J. Chem. Sot., (1960) 2423. 21 J-P. Faucher, J. Devanneaux, C. Leibovici and J-F. Labarre, J. Mol. Struct., 10 (1971) 439. 22 P. Cassoux, J-F. Labarre, 0. Glemser and W. Koch, J. Mol. Struct., 13 (1972) 405. 23 J-P. Faucher, 0. Glemser, J-F. Labarre and R. A. Shaw, C. R. Acad. Sci. Ser. C, 279 (1974) 441.
324 24 J-P. Faucher and J-F. Labarre, Phosphorus, 3 (1974) 265. 25 M. Pelissier, J-F. Labarre, L. V. Vilkov, A. V. Golubinsky and V. S. Mastryukov, J. Chim Phys. Fr., 71 (1974) 702. 26 J-P. Faucher and J-F. Labarre, Adv. Mol. Relax. Interact. Processes, 8 (1976) 169. 27 G. Levy, Actualite chimique (Paris), (1978) 23. 28 G. Levy and J-F. Labarre, Bull. Union Physic. (Paris), 1982, in press. 29 E. Mataushima, Y. Umeno, T. Marunaka and H. Akagi, J. Chromatogr., Biomed. Appl., 1982, in press. 30 F. Sournies, Ph. D. Thesis, Paul Sabatier University, Toulouse, France, 1980. 31 R. Lahana, F. Sournies, J-F. Labarre, S. Cros and G. Francois, J. Chim. Phys. Fr., 77 (1980) 85. 32 R. Lahana, Ph. D. Thesis, Paul Sabatier University, Toulouse, France, 1981. 33 A. P. Zipp and S. G. Zipp, J. Chem. Educ., 54 (1977) 739 and references therein. 34 M. Barber, J. D. Clark and A. Hinchliffe, J. Mol. Struct., 57 (1979) 169. 35 J. C. Slater, Quantum Theory of Molecules and Solids, McGraw-Hill, New York, 1974, Vol. 4. 36 See for example, J-P. Faucher, F. Crasnier and J-F. Labarre, J. Mol. Struct., 76 (1981) 165.
THE ROLE OF AZIRIDINYL CYCLOPHOSPHAZENES AND RELATED COMPOUNDS AS ANTICANCER AGENTS. A TENTATIVE QUANTUM MECHANICAL APPROACH
GUY GUERCH, JEAN-PAUL FAUCHER, and JEAN-FRANCOIS LABARRE*
MARCEL GRAFFEUIL,
GASTON LEVY
Laboratoire Structure et Vie, Universite' Paul Sabatier, 118 Route de Narbonne, Toulouse Cedex (France)
31062
(Received 28 September 1981)
ABSTRACT The electronic structures of the various conformations and allotropic species of two promising anticancer drugs, namely MYKO 63 and SOAz, have been calculated using the CNDO/P approximation. The results allow prediction of the acidity (in the Lewis sense) of the aziridinyl-bearing atoms of the drugs which corresponds to the optimum anticancer activity possible upon coordination to DNA, as the Lewis-base target. INTRODUCTION
The interest in inorganic ring systems as anticancer drugs, initiated by Cemov et al. [l] in 1959, was recently revived by the discovery of the effectiveness of some aziridinocyclophosphazenes, N3P3Azd(MYKO 63) and N4P4AzS(MYKO 83) [ 2-41, and of some aziridinocyclodiphosphathiazenes (NPAz,),(NSOX) (SOF, X = F; SOPHi, X = Ph; SOAz, X = AZ) [ 5,6] on a wide variety of animal tumors, i.e. P388 chronic leukemia, L1210 acute leukemia, subcutaneous B16 melanoma, ependymoblastoma, osteosarcomas, line 26 colon carcinoma, Lewis Lung carcinoma, P815 Mastocytoma, line 26 mammary carcinoma, lymphomas, lymphosarcomas and Yoshida sarcoma. The most efficient drugs were in each case MYKO 63 and SOAz and so we attempted to elucidate the targets of their wide activity. Assuming DNA to be on,e such target, we first investigated the nature and intensity of the interactions in vitro between MYKO 63 or SOAz and DNA by the Scatchard technique using ethidium bromide as a probe [ 71. Thus it was found that MYKO 63 and SOAz do interact with DNA but we were unable to determine at what sites on DNA MYKO 63 and SOAz interact. However, the nature of these sites could be discriminated by Raman spectroscopy: MYKO 63 was found to interact in vitro essentially as a dialkylating agent on N7 and NH2 sites of adenine [8] whereas SOAz would interact *To whom any correspondence 0166-1280/82/0000-0000/$02.75
should be addressed. o 1982 Elsevier Scientific Publishing Company
318
preferentially, in the manner of an intercalating drug, on some specific oxygen atoms of the DNA ribose-phosphate backbone [ 91. Both types of interactions proceed through the following pathway: aziridinyl rings generate electrophilic carbocations which bind themselves to the nucleophilic sites of DNA mentioned above. Thus, assuming this mechanism to be the right one, it was considered possible to undertake a quantitative study on this basis of electronic structures and charge distributions in the ground state of MYKO 63, SOAz and related compounds. This report deals with the calculation of these electronic structures by the SCF-LCAO-MO technique within the CNDO/B approximation of Pople and Beveridge [lo] which has been widely used previously for similar investigations [ 111 . MOLECULAR
STRUCTURES
AND COMPUTATIONAL
DETAILS
Calculations were performed on the whole set (minus one, see below) of X-ray molecular structures which had been observed both for MYKO 63 and SOAz under various conditions. When MYKO 63 is crystallized from CC14,the single crystal belongs to the space group C2/c and the structure corresponds to the complex N3P,Az,*3CC14 [ 121. The geometry of the N3P3Azgmoiety is depicted in Fig. 1. When MYKO 63 is crystallized from C6H6, however, the situation is quite different (space group Rz, 2N3P3Az6C6H6) and the molecular structure of N3P,Az, contained here differs noticeably (Fig. 2) from the previous one, essentially as regards the relative conformations of the aziridinyl wings [ 13, 141. Calculations could not be performed, however, owing to the uncertainty of the locations of the H atoms in the MYKO 63 molecule. A quite distinct structure is, yet again, observed when MYKO 63 is crystallized from CS? (space group P212121) or from m-xylene (space group P2/c), the two actual mblecular structures of N3P3Azgbeing strictly identical however (Fig. 3) [15].
Fig. 1. Charge densities and Wiberg indices in MYKO 63 when recrystallized
from Ccl,.
319
Fig. 2. Molecular pattern of MYKO 63 when recrystallized from C,H,.
Two allotropes exist for SOAz [16] : SOAz 1; m.p. = 83°C [ 171, space group P212121, Z = 4 (Fig. 4) and SOAz 2; m.p. = 105°C [ 171, space group P21/c, 2 = 8, with two sets of crystallographically independent molecules, namely SOAz 2A and SOAz 2B (Figs. 5 and 6). The geometry of thiotepa, SPAz3, was described by Subramanian and Trotter [ 181 (space group P2Jc, 2 = 4) (Fig. 7). Electronic charges were computed using Mulliken’s population analysis and bond orders are those by Wiberg’s definition [ 191. ELECTRONIC STRUCTURES
Charge densities and Wiberg indices are collected in Figs. 1 and 3-7. The electronic structures of the five ring systems illustrate the classical Dewar’s islands model [20] in a similar way to that previously described for other cyclophosphazenes, cyclophosphathiazenes and derivatives [ 21-261. Table 1 lists some relevant charges of interest, namely the average values on the nitrogen atoms of the AZ groups linked to P (Q1), the nitrogen atom
Fig. 3. Charge densities and Wiberg indices in MYKO 63 when recrystallized from mxylene (or CS,).
320
Fig. 4. Charge densities and Wiberg indices in SOAz 1 (m.p. = 83°C).
of the AZ group linked to S (Q?) and on the P endocyclic atoms (Q3). It can be seen that Q1 and Qz remain constant throughout the series whereas Q3 increases from 4.64 f 0.01 for the five inorganic ring structures to 4.81 in thiotepa. Hence, the phosphorus atoms in MYKO 63 and SOAz are much more acid (acidity being measured by the lack of electrons in the molecular structure) than those in thiotepa. ELECTRONIC STRUCTURE AND ANTICANCER
ACTIVITY
A critical survey of the various modes of action of anticancer drugs with proteins, enzymes and nucleic acids (DNA, RNA) shows the presence of a common Lewis acid-base mechanism [ 271. In other words, the effectiveness of both the so-called “dialkylating and/or intercalating versus DNA” anticancer agents and of the carcinogenic chemicals depends on their ability to generate acidic (i.e. electrophilic) moieties which inhibit DNA replication by linking to DNA basic (i.e. nucleophilic) sites. Thus, the activity of any anticancer agent may be described by a coordination chemistry process involving the coordination of a Lewis acid drug on a Lewis base (i.e. DNA, assuming this to be the target) [28].
Fig. 5. Charge densities and Wiberg indices in SOAz 2A.
321
Fig. 6. Charge densities and Wiberg indices in SOAz 2B.
This novel account of mechanisms for anticancer effectiveness allows a tentative explanation of MYKO and SOAz anticancer properties to be proposed: these molecules both comply with the two following necessary conditions for optimal anticancer activity. (i) The molecular structure contains a backbone (N3P3 or NJPzS inorganic ring) stable enough relative to metabolisation to transport the drug to the target [29]. (ii) The molecular structure contains five or six ligands (aziridinyl “wings”) which can provide, in vivo, suitable electrophilic carbocations for coordination to nucleophilic sites of DNA through inter- and/or intra-cross-linkings [ 30-321. Moreover, the charge densities on the endocyclic AZ-bearing phosphorus and sulfur atoms of these drugs confer to these atoms an optimal acidity for anticancer activity when compared to other AZ-bearing drugs, i.e. thiotepa. MYKO and SOAz are more effective on any animal tumor than thiotepa and such an enhancement of activity can be reasonably related, in terms of electronic structure, to the higher acidic character of P (Q_r = 4.65) in MYKO and SOAz versus that in thiotepa (Qr = 4.81). In other words, anticancer activity depends on a convenient acidity of AZ-bearing P atoms which is maximal for an electron deficiency of about 0.35. This assumption is supported by the fact that the bis(aziridiny1) derivative of Rosenberg’s c&platinum (Fig. 8) exibits only poor antitumor properties. The structure of this Pt derivative shows that aziridinyl ligands are bonded to the platinum by way of their nitrogen lone pairs [33] and thus that these AZ
Fig. 7. Charge densities and Wiberg indices in thiotepa.
322 TABLE 1 Average charges onN(Az) linked to P(Q,), onN(Az)linked
to S (9,)
and on Patoms (Q,)
Drug
Q,
Q,
Q,
MYKO 63 (from Ccl,) MYKO 63 (from xylene) SOAz 1 SOAz 2A SOAz 2B Thiotepa
5.18 5.18 5.17 5.18 5.17 5.16
5.16 5.14 5.15 -
4.65 4.64 4.63 4.63 4.63 4.81
wings cannot be opened in vivo to provide carbocations, such a mechanism requiring the availability of the N lone pairs. Hence the poor anticancer effectiveness of (AzH),PtC12 is due to the lability of chlorines in the cis configuration in the same way as in c&platinum itself, the AZ wings playing no part. The question now arises as to why aziridine substitutes the two NH3 ligands of &-platinum (DDP) rather than the chlorine atoms through HCl elimination. An answer is provided on the basis of the DDP electronic structure as calculated recently by Barber et al. [34] using Slater’s SCF-Xol method [ 351. This structure shows that the charge density on platinum is 77.0025, conferring on this atom a very acid character (the electron deficiency = 0.9975). In this case, the Pt carrier is so acidic that the bonding of aziridine occurs preferentially through a coordination process involving N lone pairs rather than through a covalent Cl/Az substitution. Hence, (AzI-D2PtC12 does not fulfil the two conditions necessary for anticancer activity mentioned above as a consequence of the over acidic nature of the Pt backbone.
r”\
NH
Cl
Fig. 8. Molecular structure of (AzH),PtCI,.
323 CONCLUSION
It is possible to estimate that an electron deficiency of ca. 0.35 on Azbearing atoms corresponds to the highest antitumoral activity observed. As soon as the acidity of such atoms deviates from this value, either to higher or lower values, anticancer effectiveness decreases. Quantum calculations on new potential anticancer molecules are now in progress in order to support our assumption [ 361. If it is correct, then quantum mechanics could provide a time and cost effective method of screening new drugs with perhaps better anticancer activity even than MYKO and SOAz. REFERENCES 1 V. A. Cernov, V. B. Litkina, S. I. Sergievskaya, A. A. Kropacheva, V. A. Pershina and L. E. Sventaitkaya, Farmakol. Toksikol. (Moscow), 22 (1959) 365. 2 J.-F. Labarre, S. Cros, J.-P. Faucher, G. Francois, G. Levy, C. Paoletti and F. Sournies, Proceedings of the 2nd International Symposium on Inorganic Ring Systems (IRIS), Gottingen, Gesellschaft Deutsches Chemiker, 1978, p. 44. 3 J-F. Labarre, J-P. Faucher, G. Levy, F. Sournies, S. Cros and G. Francois, Eur. J. Cancer, 15 (1979) 637. 4 EORTC results from B. W. Fox (Manchester) and F. Spreafico (Milano) (1980). 5 J-F. Labarre, F. Sournies, J. C.Van de Grampel and A. A. Van der Huixen, ANVAR French Patent No. 79-17336, July 4, 1979; world extension July 4, 1980. 6 J-F. Labarre, F. Sournies, S. Cros, G. Francois, J. C. Van de Grampel and A. A. Van der Huizen, Cancer Lett., 12 (1981) 245. 7 J-L. Butour, J-F. Labarre and F. Sournies, J. Mol. Struct., 65 (1980) 51. 8 M. Manfait, A. J. P. Alix, J-L. Butour, J-F. Labarre and F. Sournies, J. Mol. Struct., 71 (1981) 39. 9 M. Manfait and J-F. Labarre, Adv. Mol. Relax. Interact. Processes, 21(1981) 117. 10 J. A. Pople and D. L. Beveridge, Approximate Molecular Orbital Theory, McGraw-Hill, New York, 1970. 11 J-F. Labarre, Struct. Bonding (Berlin), 35 (1978) 1 and references therein. 12 J. Galy, R. Enjalbert and J-F. Labarre, Acta Crystallogr., Sect. B, 36 (1980) 392. 13 T. S. Cameron, C. Chan, J-F. Labarre and M. Graffeuil, Z. Naturforsch., Teil B, 35 (1980) 784. 14 T. S. Cameron, M. Graffeuil and J.-F. Labarre, Acta Crystahogr., Sect. B, 38 (1982) 168. 15 T. S. Cameron, J. C. Van de Grampel, A. A. Van der Huixen and J-F. Labarre, Acta Crystahogr., Sect. B, 38 (1982) in press. 16 J. Galy, R. Enjalbert, A. A. Van der Huizen, J. C. Van de Grampel and J-F. Labarre, Acta Crystallogr., Sect. B, 37 (1981) 2205. 17 J. C. Van de Grampel, A. A. Van der H&en, A. P. Jekel, D. Wiedijk, J.-F. Labarre and F. Sournies, Inorg. Chim. Acta, 53 (1981) L169. 18 E. Subramanian and J. Trotter, J. Chem. Sot. A, (1969) 2309. 19 K. A. Wiberg, Tetrahedron, 24 (1968) 1083. 20 M. J. S. Dewar, E. A. C. Lucken and M. A. Whitehead, J. Chem. Sot., (1960) 2423. 21 J-P. Faucher, J. Devanneaux, C. Leibovici and J-F. Labarre, J. Mol. Struct., 10 (1971) 439. 22 P. Cassoux, J-F. Labarre, 0. Glemser and W. Koch, J. Mol. Struct., 13 (1972) 405. 23 J-P. Faucher, 0. Glemser, J-F. Labarre and R. A. Shaw, C. R. Acad. Sci. Ser. C, 279 (1974) 441.
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