Antitumor activity of steroid-containing platinum (II) complexes of 1R,2R-cyclohexanediamine and 2-(aminomethyl)-cyclohexylamine isomers against leukemia L1210

Biomed. & Pharmacother., 43 (1989) 261-264 BBEkvier, Paris

261

titumor activity of steroid-containing complexes of I ,2&cycIohexaned and 2-(aminomethyl)-cyclohexylamine isomers against feukemia IA210 Y. KIDANI ‘*, M. SUZUKI*,

M. NOB ’ and T. TASHIRO 3

’ ~epar~rn~~t of Pha~acy, Tokai Teishin ~~spi~a~, ~arsu6ara~ho, Naka-ku, Nagoya 460, Japan: and 3 Cancer Chemotherapy Certfer, Japanese Foundation for Cancer Research, l-1 7-l Kami-Ikebukuro, Toshima-ku, Teky~ I70, Japan (Receiired 23 November 19&!!;accepfed t March I985?)

Summary -

Various steroid-containing platinum (Pt) complexes of IR,2R-cyclohexanediamine (= ZR,ZR-dach) and cis-dl- and frans-dl-2-(aminomethyl)cyclohexylamine (=amcha) were synthesized and their antitumor activity was screened against leukemia LIZ10 according to the F%Analog Study Protocol. Among the Pt complexes prepared, Pt IR,ZR-dach complexes of cortisone, hydrocortisone, methylprednisolone, testosterone, estriol and progesterone showed very high antitumor activity. Pt complexes of cis-dl- and ffu~~~~arncha prednisolone, Pt(l7-OH-progesterone) (fruns-dl-amcha), Pt complexes of cis-dl- and rrans-dl-amcha progesterone were found to be very effective. aathumor activity i platinumsteroid complexes/ leukemia LlZlO

R&urn4 - Action anti-tumorale d’isomkes des complexes de platiae (II) avec la lR2kcyclohexaae diamiae et la 2~amino~thyI) cycl~hexy~amineet contenant des stkroides sar la Ie&mie L1210. Divers

complexes de plafine contenant des sferoides fels les complexes h la 1R,2R-cyclohexane-diamine (=lR2R-dach) et d la cis-di- et trans-dl-2 (arninoptltyl) cyclohexylamine (=ameha) onr c;thsynt&isdser leuf action anti-tumoralea hr&feftpe sur la leuehmie l.1210 conformemenf au l’rvfowle d&de des analogues du plafine. Parmi les complexes de plafine pre’pures, les complexes 1R,2R-dach de cortisone, d’hydrocwfisone, de m~f~y~~dnisolffne, de fesrostprone,d’uesfriol et de progesr&tme onr monrrd une rtis forte action anti-turnwale, Les comple.~esde plarine d la cis-dl et trans.dlamcha prednisolone, le Pr (IFOH-progesf&one) (trans-dl-amcha), /es complexes de plufine d la cis-dl- et tram-dl-amcha progesf&one se sonl Pgalemenf rtWlf?s ff& esficoees. activi:~antitamarale/ cam#exes de plafine confeaamdes sf&Giies/ kuc&mieLIZI0

* Correspondetzceand reprirtts

Y. Kidani

262

et al. and testicular cancers. Steroids employed are : (1) corticosteroid hormones : cortisone, hydrocorti-

Hatinum (II) complexes of IR.2R-cyclohexanediamine (= IR,tR-dach), and cis-dt and rrowr-dl_2-(aminomethyi)cyclohexylamine ( = amcha) showed generally high antitumor activity against feukemia ~1210, tested according to the Platinum Analog Study Protocol ‘. Employing the characteristics of metal complexes, it will be possibie to prepare various kinds of Pt complexes with higher antitumor activity and less toxicity, by modification of the leaving groups. Cis-Platin is an efficacious agent for testicular and ovarian cancers. However, it has severe side effects. Our approach is to develop effective Pt complexes for the chemotherapy of hormonedependent cancers. ethods Water-soluble antitumor Pt(oxalato) (IR,R-dach), I-OHP[2k which showed no renal toxicity and demonstrated collateral sensitivity against cis-platin resistant tumors, without indicating any cross-resistance, was previously prepared. Phase I and II clinical trials

showed that I-OHP was effective against melanoma, hepatoma, breast cancer and colorectal cancer [3], without signs of nephrotoxicity, cardiotoxicity and hematotoxicity. It was clinically effective against cisplatin resistant testicular and ovarian cancers. Speer et al have reported the ~ti~mor activity of Pt(deoxycholato)(dach) [4]. We prepared Pt(cholato)( IR.ZR-dach)NO, and Pt(cholato),( fR,2R-dach). The former mono complex was antitumor-active, while the latter his complex was inactive. bj~~oxycholate complex, Pt(deoxycho1ato)2(IR.2R-dach), was then prepared and was found to be antitumor active. With the aim of preparingorgan-specific antitumor Pt complexes, and after selecting the drug delivery system, we prepared steroid-containing platinum(H) IR.2R-dach,and cis-dl- and trans-drlamchacomplexes, modifying the leaving groups with various steroid hormones. Androgenic steroid hormones may be effective against breast and ovarian cancers, and estrogenit steroid hormones may be effective against prostatic

* Anlitumor activity was screened against leukemia Ll210. Lt210 Ceik& IO5 were inoculated intraperitonealily into a CDF,

mouse; each group consisted of 6 mice. Pc complexes were administeredon days I. 5 and 9 i.p. The results were evaluated alter30days on the basis of survival. Antitumor activity was expressed with TK x lOO( %). as the median survival lime of treated mice. and C that of the untreated control. A dose in which the TC % value was < 85 % or the body weight of a mouse decreasedby >4 g was designated as a toxic dose.

sone, prednisone, prednisolone, methylprednisolone and methylprednisolone propionate; (2) androgenic hormones : l7-hydroxy-a-progesterone, testosterone, testosterone propionate and androsterone; and (3) estrogenic hormones : a) follicle hormones : estriol and estrone, and b) corpus luteum hormones : progesterone.

esults

In this paper, we report the screening data of the antitumor active steroid-containing Pt complexes of iR,2R-dach, c&d& and rra~~-d~amcha prepared against L1210 leukemia according to the Pt Analog Study Protocol. For the comparison, the antitumor activities of cis-diammine and ethylenediamine Pt(II) complexes of cortisone and hydroco~isone were tested in a similar manner and were found to be very low. In the eis-platin treatment, prednisone and methylprednisolone are used as antiemetics. We synthesized various Ft steroid dach and amcha complexes. Among the corticosteroid hormones, Pt(cortisone)( I R,2R-dach) showed higher antitumor activity of T/C 337 %; 5 out of 6 mice were cured, at a dose of 12.5 mg/kg. Pt(hydrocortisone) (IR,2R-dach) showed T/C 402 % at a dose of 6.25 mgfkg and all mice were cured. Both prednisane and predniso~one Ft complexes of IR.ZR-dach showed T/C 3 16 % and T/C 306 %; 2 and 3 mice respectively were cured, at a dose of 12.5 mg/kg. Pt(methylprednisolone)( IR,2Rdach) showed T/C 314 %; 4 mice were cured at a dose of 25 mg/kg, while Pt(prednisolone) (cjs-do-amcha) showed T/C 335 %; 4 mice were cured at a dose of 12.5 mg/kg. Regarding male hormone Pt complexes, Pt( 17-OH-progesterone)( IR,ZR-dach) showed T/C 189 %; I mouse was cured at a dose of 3.12 mg/kg. Though the chemical structure has not yet been disclosed, at a dose of 12.5 mgfkg, showed Pt(androsterone)( 1R,2R-dach) T/C 186 %; 2 mice were cured. Pt(testosterone)( IR,dR-dach) and its propionate complex showed T/C 3 14 % and 319 %; 4 mice were cured in both cases at a dose of 12.5 mgfkg. Pt( 17-OH-progesterone){ ~~a~s~~arncha) showed T/C 353 %; 5 mice were cured at a dose of 12.5 mg/g, but the antitumor activity of Pt( 17-OH-progesterone)(cis-dl-amcha) was not as high. Regarding female hormone Pt complexes,

Pt contplexes and

anri-tumor acrivjty

263

Table I. Antitumor activity of Pt (steroid) (1R,2R-dach) NO3 together with that of diammine and ethylenediamine

Pt(II) complexes of corticosteroid hormone against leukemia Ll210. Complexes

Dose (mg/kgj 50

Pt(NO,h (IR,2R-dach) Pt(cholato) (dach) (NO,) Pt(cholato),(dach) 103 ~(deoxycholato)~(dachj 139 pt(cortisonej (dach) (NO& Ft(hydrocortisone) (dach) (NO,), Pt(prednisone) (dach) (NOJ? ~~prednisoione) (dach) (NO,)? Pt(Me-prednisolone) (dach) (NO,): Pt(Me-prednisolone propionate) (dach) (NO,), Pt(androsterone j (da&) (NO& Pt(testosterone) (dach) (NO,): Pt(testosterone propionate) (dach} (NC&j2 ~(17-OH-progesterone) (dach) (NO,), Pt(estrio1) (dach) (NO,)? Pt(estrone) (dach) (NO& ~~progestero~e) (dach) (NO,)? Pt(cortisonej (NH& (NO,): Pt(hydrocortisone) (NH,): (NO,), Pt(cortisone) (en) (NO,): ~(hydro~~isone) (en) (NO,),

197 113 &!J 0 0

25 T/C %

12.5

6.25

3.12

100 168 101 123 0 z.4(4) r%B3j 0 0

z%(4) &E 101

sx3)

-231(l)

0 0

0

0 0 0 0 0 0 T107 0

0

122 O(2) ‘124 0 T113 0 158 Tz;; -143 156

1.S6

0.78

337w 5YXW z.!m) 306(3) 302Q) J!&!(3) @x21 314(4) 319(4) 168 203(2) z&w) 3fi2w 179 127 129

139 G(4) z!$!(lj 345(4j

189(l) 230 149

136

234(l)

137

-128

i8n

4

127

Underlining indicates positive effects (T/C am I 125). T indicates toxicity. Numbers in parentheses indicate cured mice (or mouse) out of 6 mice at 30d observation. Table II. Antitumor activity of R(H) steroid complexes of cis-df- and rruns-dlamcha against leukemia L1210. Doses (mg/kg) 50

6.25

3.12

260(l) 164

142

223(l)

262(l) z&?(t) 240

234(l)

173

Igs @

158

2fi2(2j 222(l) 268(2j 314(4) 217(2) Z(l) z!.!(1) r=(3) 2298(2) 337(5j

30013) 244(2) E(l) S(4j 23362) 278(2) 143 238(2) 353(5) 313(4) Z(2) -

25

1.2.5 T/C %

Pt(cortisone) (cis-dlamcha) (NO,): Pt(cortisone) (trans-dl-amcha) (NO,), ~(hyroco~isone~ (ci~-d~~rncha~(Nqt)? Ft(hyrocortisone) (trans-dbamcha) Pt(prednisone) (cis-dl-amcha) (NOJ): Ptfprednisone) (rrans-dl-amchaj (NO,), ~(prednisolone~ (cis-dtamcha) (NO,): Ft(prednisolone) (rrans-dl-amcha) (NO,): Pt(Me-prednisolone) (cis-dl-amcha) (NO,), ~(Me-prednisolone~ (~~uff~-~~arnchaj(NO.& Pt(l?-OH-progesterone) (cis-dl-amchaj (NO& Pt(l7-OH-progesterone) (rrans-dEamcha) (NO,)? Pt(progesterone) (cis-df-amcha) (NO,)! ~(progesterone) (tr~ns~~amcha) (NO.&

262(2j ‘110 zz(2) T94 m(2)

176 ~(3) 27W) E

Underlining indicates positive effects (T/C % 2 125). T indicates toxicity. Numbers in parentheses indicate cured mice (or mouse) out of 6 mice at 30d observation.

Y. Kidani et al.

34

Pt(estriol)( IR.ZR-dach) showed T/C 358 %: 4 mice were cured at a dose of 6.25 mg/kg. In particular, Pt(progesterone) ((ran+df-amcha) showed T/C 337 %; 5 mice were cured at a dose of 25 mg/kg, while ~(progesterone)(c~~-d~amcha} showed T/C 3 I3 %; 4 mice were cured at a dose of 12.5 mg/kg. The chemical structures of the steroid compiexes which provide the t7-OH group are tentatively postulated and the binding is considered to be rather WeaK. 17-OH steroids were reported to form chelates with transition metals [S]. Therefore, Pt complexes are considered similarly to form chelates between the 17-OH group and Co ketone group of steroids.

toxic than Pt cis-dl-amcha complexes, and optimum dose of Pt cis-dl-amcha complexes was a half of Pt rrans-dI-amcha. We are planning to further investigate the effects of these Pt complexes in hormone dependent tumors.

This work was supported in part by Grants-in-Aid from the Ministry of Education, Science and Culture, Japan. QWPthanks are also due to Tanaka Kikinzoku Kohgyo Co. Ltd.

References Fisher J.M. (1961) Adrenocortical activities of 20-cobalto-I-hydroco~iso~e and cobaltous chtoride. J. Pharmacol. Exp. Zi%er.132, 232 Kidani Y., Noji M. & Tashiro T. (1980) Antitumor activity of platinum (II) complexes of 1,2-diaminocyclohexane isomers. Gann 71, 637 Math& 6., Kidani Y., Triana K.. Rrienza S., Ribaud P., Goldschmidt E., Ecstein E., Despax R., Musset M. & Misset J.L. (19g6) A phase I trial of trans-ldiaminocyclohexane oxalato-platinum (I-OHP).

* (NOg)2

Fig. t. Proposed swucwe dach ).

for

P1(l7-OH-steroid)

(IR.?R-

Biamed. Pharmacorher. 40, 372

Ft progesterone complex contains Czo= 0 group, which may be coordinated [I]. Testosterone and estriol possess OH groups and androstecone and estrone possess ketone groups. The oxygen atoms are considered to participate in the bonding, though they are weak. Generally Pt rrujzs-dl-amcha complexes are less

4

Ridgway H.J., Speer R.J., Hall L.M., Stewart D.P., Newman A.D. & Hill J.M. (1977) Analogs of sulfato 1,2-diaminocyclohexane platinum (II). 1. Moditications in leaving ligand. J. C/in. Oncol. Hematol. 7,

220 5 Wiesei L.L. (1951) Metal chelation in the mechanism of action of gtucogenic corticosteroids. Metabolism 8, 256