CONTENTANDSTRUCTUREOFTHE CHEMISTRY COURSE: New Approaches "It is a stern, but perhaps not completely groundless assertion, based on the argument that all too many of the new approaches to instruction, while eliminating some old evils and instituting some exciting new activities, have tended to exclude or markedly diminish some of the more valuable facets of traditional approaches." 49,721 (1972) conrerence an ~aboratoryinstructson. 1974
Lloyd N. Ferguson California State University Los Angeles. CA 90032
I
Bioactivity in Organic Chemistry Courses
With the trend of making courses more relevant, organic laboratory classes have increasingly synthesized commercial substances such as drugs, cosmetics, condiments, insecticides, etc. Many of these experiments were first presented in this Journal. Also, recent textbooks are inserting more sections or mini essays on applied organic chemistry. These include, for example, the topics pesticides, prostaglandins, pheromones, perfumes, herbicides. hallucinogenic d r u"m. carcinogens, etc. One emaging topic with grow&g interest is hioactivitv of organic compounds. There are a t least three wavs in which it has been iniroduced. One is to point out a typical hioactivity of a given functional group. A second is to discuss bioorganic mechanisms. A third is to draw structure-activity correlations (SARI. This paper will briefly present examples of these three approaches. Antibacterial Activity of Hydroxy Compounds
The antibacterial activity of hydroxy compounds is often cited, with alcohols being less potent than phenols. Dilute phenol solutions (carbolic acid) were used in the 19th century as an antiseptic, but this usage has been replaced by alkyl- and halophenols, which are more effective.
""dCHH
Thvmol Mouthwash germicide
Germicide in .'rubbing aleohol"
46 1 Journal of Chemical Education
OH
Chlorophene Antiseptic and disinfectant
"$ "*,& CI
CI CI Pentachlorophenol Fungicide: used on houses as wood preservative; 2nd most widely used pesticide.
CI C CI CI Hexachlol'ophene Skin germicide
k
CHICHACH,
Hexylresoreinol Topical antiseptic
All of these phenols are harmful to the skin when concentrated, some more so than others. For instance, the toxic agents of poison ivy and poison oak are mixtures of 3-alkylcatechols. Carcinogenicity of Polycyclic Aromatic Hydrocarbons
A classic example of a bioorganic mechanistic study is that of the carcinogenicity of polycyclic aromatic hydrocarbons (PAH). It was recognized in the 1930's that certain PAH's are potent carcinogens whereas others are inactive. The first SAR studies were done by the Pullmans with their K-region theory ( I ) . They proposed that carcinogenic activity depends on the presence of a K-region with high olefinic character and an L-region of low reactivity. The Pullmans computed K-region electronic index values by molecular orbital theory which
accounted for the carcinogenic activity of PAH's quite well. Other MO calculations supported their work (2). bay re%ion
L-region Benz(a)anthraeene
However. it was observed exoerimentallv that PAH's do not react covalently with cellular macromolecules prior to metabolic activation. I t was orooosed hv. Boyland (3)that the in. termediaw is an nrcne oxirlc produred when mixed function oxidases I1'-4Si1J,)srr on thvparent hydrorarhm. This proposal spurred intense efforts tosynthc&e K-region and not! Kregim PAH epoxidt-s. Then, i t wns found in 1074, that whcn a K-region oxide and thc corresponding I'AH are incubated with cells and the DNA isolated, the t w o g i \ ~diftermt chrumnt~,eraohir .. . ornducts (41. The ohservatio~ithat ben7(arrn.. rene-7.8-did hinds 10DNA to n greater extent than does the narent hvdrocarhm tRP) led to the nution that the metnholir BP-7,U-oxide BP-7,s-diol sequence might be B P BP-7,s-diol-9,10-epoxide. The latter compound was synthesized and found to react with the bases in DNA and RNA to give a guanine-Na adduct.
.
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metabolites in the mutagenic and carcinogenic action of PAH's are still unclear. For instance, studies of the 7.8-diol9,lO-epuxide d henz~a~pyrene have shuwn that [he stereuisomer in which the I~rnzylic;-OHand the oxiranr ring are ris ( s v n ~is the most reactive toward rhiols 113) and baaicor neutral water (14), possibly owing to anchimeric assistance (13) by intramolecular H-bonding (15). On the other hand, the diastereomeric anti isomer, in which the benzylic OH and eDoxide rine are trans. is the most reactive when acid catalvzed (if?). Also, the ratio of DNA-attached syn or anti B P d i z epoxide depends on the time at which DNA is analyzed. At early times, the syn adduct predominates whereas later, the anti isomer is the major adduct (17). Finally, there are perplexing empirical observations such as: I is one of the strongest carcinogenic hydrocarbons (18)
CH, 7.12~Dimethylbenz(a)anthrsesnelI)
Substitution of a methyl group a t the 1,2,3, or 5 position of I results in inactive compounds whereas substitution of a methvl erouo at nositions 4. 6. 9. or 10 vields active compounds.kthbughb.7-dimethylben~(a)antkraceue is inactive, 4-fluoro-7-methvl- and 4-fluoro-7.12-dimethvIbenz(a)an.. thracene are active. This observation leads to the third way in which bioactivity is introduced in the organic class. Structure-Activity Correlations Foreign " molecules react with the normal hioloeical molecules in a variety of ways: (1) Covalent bond formation, as done by the alkylating anticancer drugs and the carcinogenic PAH's. (2) Chelation, such as occurs with the dithiols used for the treatment of heavv metal ooisonine. - .(3) Intercalation, as observed for the antrcancer agent adriamycin or the antibacterial acridine drugs. (4) Chemoreceptor interaction, as believed to he the mode of action of the substances we taste and smell and of many psychoactive drugs. (5) Antimetabolite action, as exhibited by the antibacterial sulfa drugs and some of the anticancer drugs, e.g., 5-fluorouracil and methotrexate. (6) Charge-transfer and inclusion complexation (24), which processes are less firmly demonstrated than the other mechanisms. The bioorganic mechanism of chemoreception is usually unknown, hut it is useful to think in terms of a hioreceptor having a fluid structure which can complement that of the substrate for ootimum interaction. The structures of compounds with substantial hioactivity are discerned by trial and error. often startine with a substance isolated from a natural source. Then, structural features which enhance or decrease activity are listed (19). An example follows. The Babylonians used opium as early as 3000 BC to relieve pain. Morphine was isolated from opium in 1803 and codeine from it in 1832. Heroin was synthesized in 1898. All three are addictive analpesics. Hundreds of structural modifications have been made in attempts to find a nonaddictive analgesic. Several useful compounds emerged with varying analgesic powers hut each &ith side effects such as hallucinations,
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anti BP-7.8-diol-9.10-e~00idd I
This compound is identical to the in uiuo product found from microsomal oxidation of BP (5).Wood et al. have shown that the in uiuo and in uitro rates of tetraol formation from diol epoxides for benz(a) anthracene (6) and henz(a)pyrene (7) correlate well with their mutagenic potencies. These results suggest that, for these hydrocarbons, alkylation of nucleic acids proceeds by a mechanism which parallels their nonenzymatic hydrolysis. Among several pairs of diastereomeric diol epoxides of benz(a)anthracene, the 3,4-diol-1,2-epoxideis by far the most mutagenic and tumorigenic. This finding led Jerina to suggest that diol epoxides with the oxide in the "bay region" may be the ultimate carcinogenic species of PAWS (8).This hay region hypothesis has been supported by similar results with other PAH's (9).
Now, a vast amount of mechanistic studies are being made on diol epoxides with respect to the kinetics of their reactions with nucleophiles and cellular constituents. The usual techniques of measuring suhstituent, isotope (lo), solvent (11), and conformational (12) effects are made. However, the roles of syn and anti diol epoxides, K-region epoxides, and other
nausea, respiration difficulties, addiction, or other adverse reactions. From these SAR studies, it has been deduced that for analgesic activity, there must be a phenyl ring at the Volume 57, Number
1.
January 1980 1 47
quaternary carbon b two carbons from a tertiary nitrogen atom. There is maximum activity when the groups are locked into a diaxial piperidine ring conformation. Some useful members in this family are the following: CH,
I
*
H
Methadone
into class. Almost all organic teachers know about or are pursuing some i n t r i p ~ i n g S correlation. ~~ The rnthusiasm that he,she.;bou,sfor themarerialexcitestheinterest ofstudents and is most effective in motivating them to study. Of course, the mechahism of carcinogenisis by PAH's would not he taken up in its entirety, but several pa& provide relevant examples for subtopics normally covered, such as conformational analyses (12), nucleophilic substitution (10,13,14), or the synthesis of epoxides and glycols (23). As biomechanisms of compounds in biological systems are further elucidated, the bioactivity of organics will increasingly be discussed. It will then be common to take up the bioactivity as well as the chemical and physical properties of organics. ~~
~
Addicting analgesic w i t h m i l d e r withdrawal s y m p t o m s t h a n morphine
The author is grateful for support from the Minority Biomedical Research Program of the National Institutes of Health, Grant No. RR 08101-08. Llterature Clted
R o p o x v p h e n e (Damon) W e a k l y analgesic: n o t a d d i e t i v e
Dextromethorphan Nonanalgerie c o u g h suppressant
(1) Pullmsn.A., Pullmsn, B., Ad". Cancer Rex., 1971.3.129. (2) Kier, L. B., "MoiecuhOrbitalTheoriin Drug Resoar&: AeademicPrrss,NewYork. 1971, p. 129: Hemdon, W. C.. Tlonr. Neu York Amd. Sci., 1974,36,2W. (3) Boyland, E.,Biaehrm. Soc Symp., 5.4 (1950). (4) Jerins.D.M..Dalv... J. W..Scirncs IRE.171119741 i s weins& I.B., Jeffrey,A. M., JennetU,K. W.,Blobrtein. S.H., Harvey,R. G..Herris, C.,Autrup, H.,Kassi, H.,endNakanishi, K..Science 193,592i1976). ( 6 ) Wmd, A. W., Chanp, R. L.,Levin, W., Lehr, R E.,Sehadet-Ridder, M., Karle, J. M., Jerina.D. M., Conney,A. H.,Proe. Not1 Acod. Sei. U.S.A. 1977,74,27&-2760. (7) W d , A. W., Levin, W . Lu, A. Y. H..Hyan. D., West, S.B., Yagi,H.,Mah, H. D., Jerina, D. M., Conney,A. H., Moi. Pharmocol. 1977,13,11161125. (6) W d , A . W.,Levin, W.,Lu.A.Y. H., Ryan,D., Wesi,S.B.,Lehr. RE., khaefcr.Rldder, M., Jerina, D. M.. Conney, A. H., Bioeham. Biophya. Ros. Commvn. 1976.21.680-
.~
~
"-". cmc
Pentamcine G o o d analgesic, weakly a d d i c t i v e : o c c a s i o n a l nausea a n d h a l l u c i n a t i o n
Often, the SAR empirical observations can be placed on a quantitative basis (QSAR). The most widely used QSAR method is that of Hansch (20) but several others are being developed, e.g., pattern recognition (21) and molecular orbital and quantum chemical treatments (22). Slowly these QSAR approaches are gaining the confidence of medicinal chemists and are providing some predictability of hioactivity of molecules foreign to biological systems.
191 Tierney,B., Hewer.A..Walsh,C.,Gn~ver.P.L..Sima.P..Chem.-Bin1 Inirmrl. 1977, 18,179-193:Thakker.D. R..Levin, W.. Wwd.A. W.,Cunney.A.H.,Sismine.T.A.. Jerina. D. M., J. Amw Chrm Soc. 1873. 100,641-667: Wood, A. W.. Lou!". w., Chan&R.L., Karie,J.M..Msh.H. D.,Yagi.H..Jerina,D.M.,Cc~nnoy,A.H..AA(.R Abrtr 1978,lOR: Wood, A. W., Levin. W..Ryan. D.,Th
