Equations fit drugs' anticancer activity MEDICINAL—Linear equations re lating chemical structure and biological activity seem to hold for cancer drug action as well as for other pharmacological systems, according to Dr. Corwin Hansen of Pomona College, Claremont, Calif. Speaking in a sym posium on cancer chemotherapy, Dr. Hansch described results of process ing data previously given by other in vestigators to the National Cancer In stitute (NCI), Bethesda, Md. Lipophilicity is one of the most im portant factors in drug effectiveness, he thinks (C&EN, April 12, page 34). Drugs must be lipid-soluble to reach receptor sites. Too much lipophilicity can leave drug molecules imprisoned indefinitely in lipid phases, however. Thus, Dr. Hansen's equations relate drug effectiveness—log(l/C)—to both logP and log2P, giving parabolic curves. C is the molar concentration of a compound needed to achieve a designated effect. Any standard effect can be used. Ρ is the partition coeffi cient of the drug between 1-octanol and water, and is a parameter of lip ophilicity. A useful equation in screening drugs might be log(l/C) = —kJLog*P + k2logP + k3a~ + fc;£s + k5, where σ is a Hammett substituent constant to include electronic effects, and Es is a Taft steric term. Dr. Hansch empha sizes that such an equation is not a true "field equation," which would re quire a knowledge of electron density at every position, together with a to tal description of molecular geometry. Patterns. In examining data on can cer drugs, Dr. Hansch often begins by using an equation containing only lip ophilicity terms, log(l/C) = —kJ.og2P + k2logP + k3. From broad patterns obtained, he intends later to examine fine tuning effects based on electronic or steric factors. In the aniline mustards—derivatives of N,N-bis-2-chloroethylaniline—he
finds that the governing equation is log(l/C) = -0.24/ogP - 1.45σ- + 4.36. This relation holds for data obtained with Walker 256 rat tumors. C holds for certain survival criteria set by NCI. The lack of dependence on log2P in dicates that not enough drugs of this type have been tested to find the peak of the parabola, and thus the curve appears linear over the region tested. To Dr. Hansch, this finding indicates need for more research with more wa ter-soluble compounds to reach the re gion of optimum lipophilicity. As to electronic factors, dependence on σ ~ in dicates that electron-releasing substituents in the para position—the posi tion examined—may heighten activity of aniline mustards against rat tu mors used as a model. In the case of nitrosoureas, Dr. Hansch finds that log(l/C) = -0.06log2P -O.OSlogP + 4.53. Here, mouse leukemia L1210 is the model. The re gion of known drugs gives a peak in the parabola at logP = —0.72. More work is still needed, however, since this value for logP was obtained by extrapolation and needs verification. Data available indicate that nitrosou reas that are more water-soluble would be more effective. Since lesslipophilic drugs would tend to be less toxic, toxicity of nitrosoureas might be cut at the same time. L1210 mouse leukemia is again the model for his examination of imidazolecarboxamides. He finds that log(1/C) = -027log2P + 0.54/ogP + 3.52. The ideal lipophilic character is 1.0, indicating that this class of drugs op erates through a different mechanism from the aniline mustards or the ni trosoureas. A more fat-soluble drug is needed for increased effectiveness. Influences. For future work, Dr. Hansch indicates that he will follow electronic influences in imidazolecarboxamides of lipophilicity 1.0. Using compounds synthesized under National Cancer Institute auspices, Dr. Hansch will study effects of steric and electronic terms.
Equations point to chemotherapeutic approaches Number of drugs studied
Aniline mustards against Walker 256 rat tumors log(1/C) = -0.24logP - 1.45σ~ + 4.36
Correlation coefficient
8
0.944
Nitrosoureas against L1210 mouse leukemia log(1/C) = -0.06log 2 P - 0.08logP + 4.53
17
0.953
Imidazolecarboxamides against L1210 log(1/C) = -0.27log 2 P + 0.54logP + 3.52
9
0.945
C = molar concentration of a compound required to produce a standard response in a constant time interval Ρ = partitioning constant for distribution of a compound between an organic phase and water a~ = Hammett substituent constant 46
C&EN SEPT. 27, 1971
In some work leading to the data that Dr. Hansch used, L1210 leukemia cells were injected into mouse brains, whereas drugs were given intraperitoneally. One goal of cancer chemo therapy is discovery of drugs that will cross the protective blood-brain bar rier to attack brain cancer. He says there will have to be careful work to ensure that enhanced survival times are due to cancer cells' destruction in the brain as fast as elsewhere in the body. In examining equations to pick out characteristics of drug-subject interac tions, Dr. Hansch examines coefficients to determine whether coefficients from equations governing cancer drugs are compatible with coefficients in equa tions involving drugs in other known systems. He finds good correlations indicating that cancer is tractable in terms of this mathematical analysis. When linear equations occur in drug-subject interaction analyses— lacking terms in log2P—examination of coefficients reduces to analytical geometry of straight lines, with characteristic slopes and intercepts. He finds that slopes tend to fall into two families. From information on biological processes whose mecha nisms are known, Dr. Hansch surmises that one slope belongs to interactions with membranes, while the other be longs to binding with proteins. The intercept of a linear equation is to him a measure of the pharmaco logical sensitivity of the system under examination, or of the intrinsic phar macological properties of drugs tested. Considering the same drug in the same biological test system, ef fective doses to affect 25% of ani mals at the set level, or to affect 50% of animals at that level, could be found, giving two equations. The two intercepts would reveal sensitivity to increases in drug doses. Alternatively, two classes of drugs could be compared as to intercepts. Intercepts would reveal intrinsic phar macological properties peculiar to that class, independent of hydrophobic properties of each class.
Pesticides applied with fertilizers FERTILIZER—It is a moot point whether pesticides should be considered additives to fertilizers or components forming distinct fer tilizer-pesticide combinations. Since the combination of 2,4-D with a sprayon fertilizer in 1965, the commercial growth of combinations has been growing rapidly. J. L. Strauss of Amoco Chemicals observes that one
company reported that more than 60% of its fluid tonnage fertilizer was applied in combination with various additives in 1970, although he doesn't know if this is typical. One of the problems and sometimes a limiting factor in use of fertilizer combinations is that one of the com ponents may not always be desirable. Mr. Strauss also suggests that chang ing governmental regulation could have a major role in limiting future development of combinations. The chief reason for interest in com binations is economic. It's cheaper to make a single pass with a multi purpose material than several passes, each with a single chemical. In areas where fertilizer and pesticide require ments are fairly stable, the combina tions will find increasing demand. For those areas with changing require ments and rapidly changing geog raphy, the opposite may be true. Environmental concern requires that extensive testing be done for new combinations. J. W. Young of Chemagro Corp. reports on several new combinations that are promising but still undergoing tests after being re leased for marketing. Combinations of Di-Syston (a systemic insecticide), Dasanit (a nematicide), and Baygon (a soil insecticide) with various ferti lizers are being offered, but Mr. Young is explicit about formulation and appli cation strictly for specific uses. Carriers. The safety of many pesti cides may be improved through the use of some new water-degradable carriers. At Alva Research Corp., in Oklahoma, controlled-release mate rials are being developed using poly mers formed with 2,4-D, 2,4,5-T, malathion, and other compounds. One of the novel techniques for ap plying pesticides and herbicides in volves elastomeric matrices. N. F. Cardarelli, chief scientist at Creative Biology Laboratory, Inc., Barberton, Ohio, reports that the butoxyethanol ester of 2,4-D has been incorporated in slow-release matrices and used against water hyacinth and Eurasian watermilfoil, two major aquatic weeds in the U.S. A strong argument in favor of the matrix-release application technique is the minimal contamination of the en vironment. Dr. Cardarelli cites one in stance where a continuous niclosamide concentration of 4 p.p.b. destroyed vec tor snails in three to four weeks. Nor mally at least 10 p.p.m. on a one-day treatment period would be required with a second application after two months.
-*^**fi5SS^ eth η-Butyl Sulfide (3-thiaheptanol-1) κ| \ | ι I™" r ~ i\ /Λi / /l1 2Another "Hydroxvnew y'member of the Phillips line • ^ •—
V
*
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of petro-sulfur products listed below.
MERCAPTANS (THIOLS) *Ethyl Mercaptan *iso-Propyl Mercaptan *n-Propyl Mercaptan iso-Butyl Mercaptan *n-Butyl Mercaptan sec-Butyl Mercaptan *tert-Butyl Mercaptan sec-iso-Amyl Mercaptan *tert-Amyl Mercaptan mixed-Hexyl Mercaptans *n-Hexyl Mercaptan mixed-Heptyl Mercaptans *n-0ctyl Mercaptan *tert-0ctyl Mercaptans tert-Nonyl Mercaptans n-Decyl Mercaptan n-Dodecyl Mercaptan *tert-Dodecyl Mercaptans *tert-Tetradecyl Mercaptans *tert-Hexadecyl Mercaptans Mixed Secondary Mercaptans *Mixed Tertiary Mercaptans *Cyclohexyl Mercaptan Pinanyl Mercaptans-Type 2 Pinanyl Mercaptan-Type 10
Typical Purity Wt.%
99+ 98 99+ 98 98 97 98 97 98 97 96 97 98 96 97 95 96
97 94 82 96 94-98
99+ 96 98
DIFUNCTIONAL MERCAPTANS Ethylcyclohexyl Dimercaptan TCD (Tricyclodecene) Mercaptan Anethole Mercaptan *Dipentene Dimercaptan
98 97 98 98
DISULFIDES η-Propyl Disulfide •tert-Butyl Disulfide η-Butyl Disulfide tert-Amyl Disulfide tert-Octyl Disulfide tert-Dodecyl Disulfide POLYSULFIDES tert-Butyl Polysulfide tert-Amyl Polysulfide tert-Octyl Polysulfide tert-Dodecyl Polysulfide SULFOXIDES A N D SULFONES η-Propyl Sulfoxide η-Propyl Sulfone η-Butyl Sulfoxide η-Butyl Sulfone CYCLIC SULFONES 3-Methylsulfolane 3-Methylsulfolene *Sulfolane *Sulfolene MISCELLANEOUS S-t-Butylthioglycolic Acid S-t-Octylthioglycolic Acid S-t-Dodecylthioglycolic Acid Ethylenetrithiocarbonate *Ethylthioethanol
SULFIDES Methyl Sulfide *Ethyl Sulfide Allyl Sulfide η-Propyl Sulfide tert-Butyl Sulfide *n-Butyl Sulfide
99 96-99 98
96 97 97
OTHER PETRO-SULFUR COMPOUNDS: If you don't see what you need above, let us know. We'll be happy to discuss your specific requirements.
These Petro-Sulfur Compounds are available in commercial quantities.
IPHILUPSZ Special Products Division, PHILLIPS PETROLEUM COMPANY Bartlesville, Oklahoma 74004. Phone: 918 336-6600.
66 At Phillips 66 it's performance that counts SEPT. 27, 1971 C&EN
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