the American Chemical Society
Structure-Activity Relationships in the Field
Antibacterial Steroid Acids
Institute for Medical Research, n'ew Brztnswick, Yew JerseyReceived November
The antibacterial activity
a variety of steroidal and triterpenoid acids has been determined using
Activity was found to be less dependent on specific structural andAll active compounds have
rigid polycyclic skeleton with
as the test organism.stereochemical features than had been anticipated.a carboxyl group close
an oxygen function or a double bond.
Recent investigations leading to the establishnient ofthe structure of the antibiotics fusidic acid
as tetracyclictriterpenoids closely related to the steroids have docu-mented the biological versatility of this importantnucleus
yet another area. The subsequent conver-sion of the structurally related triterpenoid acid eburi-coic acid itito an antibacterially active ring
by means of microbial enzymes6 has prompted usto undertake
Ben ;\Is). Laboratory
Cancer Research and Department
L. Allinger and
4552 (1961).(4) S.
Sano. T. Hata.
Udagawa, Y.Nakayama, and H. Yamaguchi,
was proposed by Professor
Okuda at the Symposium on theChemistry of Satural Products, Nagoya, Oct.
Abstracts of Papers,
terial properties of steroidal and triterpenoid acids.
the outset that, because of the considerabledifferences in the stereocheinistry between the naturallyoccurring antibiotics and the seco-acid
the struc-tural requirements for antibacterial activity might notprove to be too exacting. This inipression gainedfurther support when considering the fact that, whilein the steroid antibiotics the important acidic functionis located at C-21 and forms part of the side chain, thebiological activity of the seco-acid
the presence of
carboxyl group at
as demonstratedby the increase in activity attending methylation of the21-carboxyl group.7 The above impressions have beenfully borne out by the data reported in this paper.It appeared iiiost appropriate to begin such a studyby preparing additional ring
seco-acids from a varietyof sterols and triterpenes, and to assess the influence ofthe rigid portion of the steroid nucleus and of the sidechain on biological activity. These data are suninia-rized in Table I. With the exception of compounds
those listed in this table possess the
backbone characteristic of the sterols.
ever, the location of the angular methyl groups varieswidely and
does the nature of the side chain. Withthe exception of coiiipound
all of the compounds wereactive arid one can conclude from these data that con-siderable structural variation is possible without loss
antibacterial activity. This is particularly evidentwhen one considers the lupeol derivative
whichshows the most far-reaching deviation in skeletal struc-ture.
attempt is being made here to evaluate thequantitative differences in activity between the variouscompounds except in those cases where only a singlesubstituent is being varied. This
the21-methyl ester of
which shows a 30-fold enhance-ment in activity over the latter. The conclusion appearsjustified that
second anionic site at
distant part of themolecule is detrimental to activity.
is felt, on struc-
(1961): 16 (1963).(6)
Grabowich, C. de Lisle Meyers, and
The necessity for the presence of at least one carboxyl group derivesfrom the fact that the dimethyl ester of
was inactive at the
the highest level employed in this investigation. Similarly, reductionof bothcarboxyl groups to primary alcohols led to inactive compounds: