510
J. Med. Chem. 1993,36,510-512
Communications to the Editor A trans-Platinum Complex Showing Higher Antitumor Activity than the Cis Congeners
Chart I. Schematic Drawing of the Structural Formulas of the Imino Ether Complexes Me
Mauro Coluccia,*JAnna Nassi,? Francesco Loseto,? Angela Boccarelli; Maria A. Mariggio,? Domenico Giordano,? Francesco P. Intini> Paola Caputo,* and Giovanni Natile’J Dipartimento di Scienze Biomediche e Oncologia Umana, Sezione di Patologia Generale e Oncologia Sperimentale, Universitb di Bari, Policlinico, Piazza Giulio Cesare 11, I- 70124 Bari, Italy and Dipartimento Farmaco-Chimico, Universitd di Bari, via E. Orabona, 4, I-70125 Bari, Italy Received November 20, 1992
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y.0
Structure-activity relationships that define the class of antitumor-active platinum compounds were summarized in 1973.’ cis-Diamminedichloroplatinum(I1)(cis-DDP) and related analogues produce bifunctional lesions on DNA; the most common adduct is an intrastrand crosslink between adjacent guanines that has been shown to inhibit DNA replication and/or transcripti~n.~?~ More recently, platinum cations of the form [PtCl(NH3)z(Am)l+ (Am= pyridine, pyrimidine, purine, piperidine, or aniline ligand) have been proposed as a new class of platinum antitumor complexes4characterized by a monofunctional interaction with DNA, a binding mode previously unexpected to result in antitumor a ~ t i v i t y .Moreover, ~ activation of the trans geometry has been reported to occur in platinum(I1) complexes with planar ligands, [PtClzLzI (L = pyridine, N-methylimihle, thiazole, or quinoline).m These observations suggest the possibility of identifying new classes of platinum complexes structurally different from the classical analogues. We have substituted imino ether for ammine in cis- and trans-DDP and found that in the new compounds the biologicalactivity of cis and trans isomers is reversed. The complex with trans geometry shows the greatest in vitro cytotoxicity against P388 leukemia cells and displays a relevant antitumor activity on P388- and P3WDDPbearing mice. Imino ethers, like amines, are potential N-donor ligands and have a N-bound hydrogen suitable for hydrogen bond formation. They can have geometrical isomerism (E or 2) about the CN double bond so that, in addition to the possible cis and trans configurations of the platinum complex, there is additional isomerisn at the coordinated
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Me M-gz
He M-EE
isomer is favored on a kinetic ground (trans addition of the alcohol to the nitrile triple bond) while the EE isomer is favored on a thermodynamic basis. Therefore the initially formed 22 isomer isomerizes subsequently to the E2 and EE isomers in the presence of a catalytic amount of base; in the absence of base this transformation is not observed and the 22 isomer can be regarded as a stable species. cis-EE, cis-22, and trans-EE (the yield of E2 isomers was always small; trans-22,having a low solubility in water, was not investigated) were tested for in vitro cytotoxicity and in vivo antitumor activity against P388 leukemia. The in vitro inhibitory effects of increasing doses of platinum-imino ether complexes on the growth of P388 cells are shown in Figure 1. The drug sensitivity is also expressed as 50% growth inhibitory concentration, IDw. The IDw values of cis-EE and cis-22 are greater than that of cis-DDP (IDw = 2.05 pM) by a factor of 4 and 9, respectively;on the contrary,the IDm of trans-EE proved to be smaller than that of trans-DDP (ID50= 85 pM) by a factor of 40, and very close to that of cis-DDP. These results indicate that the substitution of imino ethers for ammines brings only slight changes in the activity of the cis complexes,while it has a dramatic effect on the behavior of the trans species. The reasons for the enhanced cytotoxicity of the trans-EE compound are under investigation; preliminary results indicate that trans-EE inhibits the DNA synthesis in P388 cells in vitro (unpublished), suggestinga role for DNA binding in its mechanism of action. Moreover, other mechanisms such as enhanced uptake or different reactivity with intracellular thiols might be involved.ll ligand^.^ As far as the in vivo effects are concerned, the results Platinum complexes with imino ethers are readily obtained with P388 leukemia-bearing mice (Table I) prepared by addition of alcohol to platinum n i t r i l e ~ . ~ J ~ indicate that cis-EE and trans-EE are endowed with The geometry of the metal center does not change during significant antitumor activity, while cis-ZZis inactive. The the reaction so that the cis-imino ether species are formed antitumor activity of cis-EE does not depend upon the by starting with the cis-nitrile and similarly for the trans treatment schedule, and a cross-resistance of the same isomer. The E or 2 configuration of the imino ether allows compound with cis-DDP was observed on the P388/DDP the formation of three different isomers for the cis and subline. In contrast trans-EE is more active when three for the trans isomer of [PtClz(imino etherlzl. A administered daily for 7 consecutive days (% TIC = 170) scheme of different isomers is given in Chart I. The 22 and has significant effect also on the cis-DDP-resistant subline (%TIC = 133). This is the first unambigous * Authors to whom correspondence should be addressed. evidence for an antitumor activity of a trans-platinum t Dipartimento di Scienze Biomediche e Oncologia Umana. complex. 1 Dipartimento Farmaco-Chimico. 0022-2623/93/1836-0510$04.00/00 1993 American Chemical Society
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Journal of Medicinal Chemistry, 1993, Vof.36, No. 4 511
Communications to t h e Editor complex ID50 (pM)
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rn
cis-EE
7.5
cis-22
18 2.2
0 Irons-EE
C T A G
c 0 0
0 0
0-
5
10
15
20
Drug concentration
25
30
(VM)
Figure I. Survival curves of P388 cells (105 cells/mL in exponential growth phase) exposed to increasing concentrations ofcis-EE(.),cis-ZZ(r),and t r a n s - E E ( 0 ) f o r l hat37OC.After drug removal, the cells were incubated for a n additional 48 h, and then their number and viability (trypan blue exclusion test) were assessed. Each point represents t h e mean of five experiments performed in triplicate i standard deviations. Table I. Effects of Platinum-Imino Ether Complexes and cisand trans-DDP on Mice Bearine P388 or P388/DDP Leukemian complex cis-EE
dose (pmollKg) 19.6 39.2 78.4
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