2762
WOLFGANG H. H. GUNTIiER AND HENRYG. MAUTNER
present in this temperature range, then the reversibility of the reaction D1 Dz in formate should permit determination of the equilibrium between these forms and, from the temperature dependence of the equilibrium constant] the heat of transformation may be calculated. For example, if the transformation is 90% complete in each direction a t each of the temperatures in Fig. 7, a value of AH of about 30,000 cal. would be deduced. The heat absorbed in denaturation itself for a t least one of these temperatures cannot be less than half of AH for the D, -+ Dz transformation and may be greater by an indeterminate amount. However, the protonation of 22 unmasked imidazole groups, which is incident to denaturation by acid, will appear (by its attendant heat evolution) to reduce the true AH of denaturation by about 140,000 cal. when AN is measured in other ways. The values estimated earlierI6 from the $H displacement of the equilibrium by changes in temperature have been shown to be of doubtful significance because of the complex regeneration reaction3 which involves the transient formation of an intermediate. Effect of pH on Viscosity on Denatured Protein. -Since substituting formate ion for other buffer anions in kinetic experiments on denaturation has the effect of lowering by a constant amount, the PH, a t which the same rates are obtained. i t appeared possible that the pecuiiar effects of formate ion on viscosity might be manifested in other acids a t a high PH, i.e. about 3.8-3.9. The effect of $ H on viscosity of denatured protein a t 25” a t a single ionic strength was therefore investigated. The results obtained a t three fiH values with protein denatured a t a single pH are shown in Fig. 8. (16) E. M. Zaiser and J. Steinhardt,
[CONTRIBUTION FROM
T H I S JOURNAL,
THE
2.5‘ (high E )
VOl. 82
a t p H 5 . Transforms readily to DS in formate, at pH 3 , 5 , 0’; slowly, if electrostatic
interaction
factor;
7 6 , 2SC6 (1954).
DEPARTMENT OF PHARMACOLOGY, SCHOOL OF MEDICINE, YALEUNIVERSITY, NEW HAVEN,CONNECTICUT]
Pantethine Analogs. The Condensation of Pantothenic Acid with Selenocystamine, with Bis-(p-aminoethyl) Sulfide and with 1 ,Z-Dithia-5-azepane (a New Ring System) R Y WOLFGANG H. H. GUNTHER~ AND HENRY G. MAUTNER RECEIVEDNOVEMBER 13, 1959
As part of a project concerned with the development of pvtential coenzyme A antagonists, the following compounds were synthesized: selenopantethine, bis-(P-pantothenoylaminoethyl) sulfide and N-pantothenoyl-1,2-dithia-5-azepane. These compounds were prepared by the condensation of pantothenic acid with selenocystarnine, bis (6-aminoethyl) sulfide and 1,2-dithia-&azepane, respectively. T h e last compound represents a new heterocyclic system.
I n the design of antimetabolites with potential carcinostatic activity, little emphasis has been placed on possible antagonists of coenzyme A or compounds related to it. Yet the literature contains several reports which suggest that tumor tissue might be more sensitive t o the action of ( 1 ) Part of this material was presented before the Biological Chemistry Section a t the American Chemical Society Meeting, Atlantic City, N. J., September 1959, 76-C. (2) This work was supported in part by a grant (CY-3937) from t h e National Institutes of Health, Public Health Service We are indebted t o t h e Wellcome Trust, London. Great Britain, for a generous travel grant t o W H. H Gunther. (3) James Hudson B r o a n Memorial Post-doctoral Fellow, 19581959.
antagonists of coenzyme A than normal tissue. Thus, the capacity of tumors to utilize acetate and to oxidize fatty acids appears to be lower than that of non-neoplasiic tissue, rat tumors are reported to be deficient in coenzyme A and in pantothenic acid-content, as compared to normal tissues,6 and in at least some neoplasms the coenzyme A content parallels certain synthetic capacities of the tumor.6 Reports that the utilization of acetate is the first cell function, it1 a bacterial system, to (4) J. P. Greenstein. “Biochemistry of Cancer,” Academic Press, Inc., New York, N. Y., 1954, p. 374. ( 5 ) H. Higgins, et al., Proc. Soc. E x p f l . B i d . M c d . , 7 5 , 462 (1950). (6) P. Emmelot and L. Bosch, Brzl. J . Cancer, 9 , 327 (195,5).
June 5, 1960
PANTETHINE ANALOGS KSeCN
(X) CeH6-CO-NH-CHz-CH2-SeCN
2763
CeH5-CO-NH-CH2-CH2-C1 (XI)
f---
\,OH
(XI) ( C~H5-CO-NH-CHz-CHz-Se)2 \HCI
I-/ v)
+(R-CO--NH-CH~-CHz-Se)~
(HzN-CHz-CHzSe)Z
(VI)
(11)
(H~N-cH~-cH~)~s
R-CO-O-CO-OC,H~-~
\1-
(VII) HN(
CHz-cHz-T
CH2-CHZ-S (VIII)
-1
(R-CO-NH-CH~-CH~)~S (111)
-1
:I:::
