851
J. Med. Chem. 1983,26,851-855
Quantitative Structure-Inotropy Relationship Applied to Substituted Grayanot oxins Naohiro Shirai,? Jinsaku Sakakibara,*ft Toyo Kaiya: Sawako Kobayashi,f Yoshihiro Hotta,t and Kazumi Takeyaf Faculty of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, and Department of Pharmacology, Aichi
Medical University, Nagakute, Aichi, Japan. Received August 20, 1982 Nine 14b-O-acylatedgrayanotoxins were synthesizedby ozonolysis of 14,16-alkylidenegrayanotoxh111. The correlation between positive inotropic potency (PIE) in guinea pigs and physicochemical parameters (Vw, Mw, and RmEo)in 14 14-substitutedgrayanotoxins were quantitativelyanalyzed. It became clear that a parabolic relation existed between the bulkiness of the 14-substituentsand PIE and that some electronicfactor and the hydrophiliehydrophobic balance would be related to the development of PIE. Active principles, such as grayanotoxins or asebotoxins, from some ericaceous plants are diterpenoids having complex pharmacological and toxicological manifestations in the nervous and muscular systems of various kinds of animals. The mechanism by which these toxins produce these effects involves opening Na" channels of excitable cell membranes, as shown in several electrophysical studies.ls2 In a previous paper,3 we reported on the relationship between the structure, positive inotropic potency (PIE), and lethal dose of grayanotoxins in guinea pigs. In that study it became clear that the presence of 30-hydroxy and 106-methyl groups attached to the grayanane (A-nor-Bhomo-eat-kaurane) skeleton was essential for the development of PIE and that the potency was increased by acylation of the 146-hydroxy group. Kinghorn et al.* described the structure-activity relationship of grayanotoxin derivatives using the spasmodic response of brine shrimp. They reported that 6-acylgrayanotoxin I11 (2) had some 20-30 times less activity than the mother substance, grayanotoxin I11 (G-111, 1); that 6,16diacylates (3) were 2-3 times less effective than 6-acylates (2) in LDm studies; and that the 3,6,14-triacylates 4 were inactive. The toxic activity of 14-acylates 5 was not reported because of difficulty in preparing them. For the elucidation of the structure-activity relationships of grayanotoxins, 140acylates were indispensable to get information about the role of side chain at 146-position. The aim of this paper is to clarify the degree of contribution of these compounds to PIE in isolated guinea pig papillary muscle. Chemistry. 14-Acylgrayanotoxin I11 (5) could not be obtained in the usual way: acylation of G-I11 (1) by acyl anhydrides and pyridine gave 6-acylates (2) or 3,6-diacylates (6)but did not yield 14-a~ylates.~ In contrast, 3,14-diacetyl-6-benzoylgrayanotoxin I11 (7) or rhodojaponin I (8) was hydrolyzed only at the 14-position when treated with dilute alkali6$' Recently, Terai et al. reported that ozonolysis of 5,6:14,16-diethylidenegrayanotoxinI11 (9) afforded 6,14diacetylgrayanotoxinI11 (10): This reaction was applied in our laboratory to synthesize 14-acylgrayanotoxin I11 (5). We selected 6-acetylgrayanotoxin I11 (11) as a starting material to avoid acetalization between 5- and 6hydroxygroups. Compound 11 was treated at room temperature with aldehydes (or acetal in the case of l l f ) in dimethylformamide in the presence of p-toluenesulfonic acid to afford 6-acetyl-14,16-alkylidene(orary1idene)grayanotoxin I11 (12a-9, which in the next step was submitted to alkaline hydrolysis to remove the protected 6acetyl group. The 14,16-alkylidene(or ary1idene)grayanotoxins I11 (13a-i) were then oxidized with ozone at -78 OC Nagoya City University.
t Aichi Medical University.
R'O
OH
R'
no. 1
RZ H
H H H
2
3 4 6
acyl
7 10 15 16 17 18
Ac
acyl
acyl
H H
R3 H H
acyl acyl acyl BZ Ac
acyl acyl
H
glucosyl H AC
BZ
BZ
H H
H H
H Ac
Ac
lactoyl acyl = acetyl, propionyl, butyryl, and benzoyl
OAc
8
I
14 9
to yield 1Cacylgrayanotoxins I11 (5a-i) (Scheme I). The physical and analytical data for these compounds (5) are summarized in Table I. Compound 5a was identical with (1) T. Narahashi and I. Seyama, J. Physiol. (London),242,471 (1974). (2) I. Seyama and T. Narahashi, J. Pharrnacol. Exp. Ther., 219, 614 (1981). (3) Y. Hotta, K. Takeya, S. Kobayashi, N. Harada, J. Sakakibara, and N. Shirai, Arch. Toricol.,44, 259 (1980). (4) A. D. Kinghorn, F. H. Jawad, and N. J. Doorenbos, Toxicon, 16,227 (1978). (5) A. D. Kinghorn, F. H. Jawad, and N. J. Doorenbos, J . Chromatogr., 147,299 (1978). (6) J. Sakakibara, K. Ikai, and M. Yasue, Yakugaku Zasshi, 94, 1534 (1974). (7) H. Hikino, K. Ito, T. Ohta, and T. Takemoto, Chem. Pharrn. Bull., 17, 1078 (1969). (8) T. Terai, M. Katai, N. Hamanaka, T. Matsumoto, and H. Meguri, Chern. Pharrn. Bull., 26, 1615 (1978).
0022-2623/83/1826~0851$01.50/0 0 1983 American Chemical Society
852 Journal of Medicinal Chemistry, 1983, Vol. 26, No. 6
Shirai et al.
Table I. Physical Properties of Compounds 5a-ia
no.
R
5a 5b
CZH, n-C,H, n-C,H, n-C,H,, n-CsH13 ClCH,CH,
5c 5d
5e
reaction time, h
yield,b %
mp, “C
2 2 1 2
67 60 45 72 22 29 45 63 71
194-196 201-204 178-180
1
amorph amorph
formula
anal.d
c, H c, H H;e C c, H H;f C c, H c, H c, H c, H
Cz3H3807 CuH,oO7 ~,,H,*O7 C26H4407
C’27H4607 5f 6 196-200 C23H3707a 212-215 5g C6H11 1 C,,H4,0,~0.5H,0 5h C, H5 2 198-201 C27H3807 amorph 5i (CH313C 1 C2,H,,0,*0.5H20 a All compounds were recrystallized from n-hexane-AcOEt. Yield from compounds 13. Amorph = amorphous powder. Elemental analyses are within i0.4% of the theoretical values unless otherwise indicated. e C: calcd, 66.05; found, 65.56. C: calcd, 67.19;found, 66.68.
Table 11. Positive Inotropic Effect, Lethal Dose. and Phvsicochemical Parameters OH
PD 2 no.
R
obsd (+SE)a
calcdb
14 1 17
H HO CH3CO0 C, H, COO n-C3H,CO0 n-C,H,COO n-C,H,,COO n-C,H,,COO CICH,CH,COO C6H,,CO0 C, H5COO (CH3),CCO0 CH3(OH)CHCO0
5.61 (0.06) 6.15 (0.06) 6.31 (0.04) 6.67 (0.07) 6.81 (0.06) 6.41 (0.03) 5.75 (0.06) 5.32 (0.06) 6.96 (0.06) 6.17 (0.04) 5.79 (0.04) 5.78 (0.06) 6.54 (0.09)
