Subramanian S., Ferreira M. M. C., Trsic M., “A STRUCTURE -ACTIVITY RELATIONSHIP STUDY OF NAPHTHOQUINONES AGAINST CARCINOSARCOMA WALKER 256”. Budapest, Hungary, 21-23/ 08/1997: CC'97 Conferentia Chemometrica, Book of Abstracts, Lec23 (1997). Oral L23 - Keynote Lecture.
A STRUCTURE -ACTIVITY RELATIONSHIP STUDY OF
NAPHTHOQUINONES AGAINST CARCINOSARCOMA WALKER
256
Subramanian, Shayla1; Ferreira, Márcia M. C.2 and Trsic, Milan.3
1 Departamento
de Química, CCEN, Universidade Federal da Paraíba, João
Pessoa,
PB, 58051-900, Brasil
2 Instituto de
Química, Universidade Estadual de Campinas, Campinas
SP, 13081-
970, Brasil
3 Instituto de
Química de São Carlos, Universidade de São Paulo,
13560-970, São
Carlos, SP, Brasil
Lapachol and its
analogues are known to possess antitumor,
antibiotic and
antimalarial activities. Lapachol
also exhibits antiinflammatory and
antiulceric
action. It has been shown that this drug is highly
active against Walker 256 (W256)
carcinosoma tumor in rats when parenterally or orally
administered.
MNDO-AM1 semi-emipirical
molecular orbital calculations were carried out on
lapachol and several derivatives of
1,4-naphthoquionones in order to investigate
possible relationships between electronic
structural parameters and activity against
Carcinosarcoma W256 reported
in the literature. It was found that, among
the
calculated electronic indices,
the HOMO (highest occupied
molecular orbital)
coefficients (Sci2
i = 2s, 2px, 2py and 2pz) for carbon atoms of the side chain double
bond have a significant
influence in this activity, while
the LUMO (lowest
unoccupied molecular orbital) apparently
have no importance on it.
Exploratory data analysis by Hierarchical
Cluster (HCA) and Principal Component
Analysis (PCA) for autoscaled data
consisting of 26 samples and 10 variables,
showed a clear separation of
active compounds from the inactive
ones. PC1
discriminated between active/inactive compounds and PC2
discriminates a small set
of inactive compounds. This analysis gives a strong evidence
that the activity against
W256 involves a mechanism wherein the quinone
acts as a reductor through the
participation of the p-electrons
of the side-chain double bond. HCA results confirm
the PCA presented above, suggesting that reasonable
models might be constructed.
A classification study with respect to structure-activity
using the KNN (K-Nearest
Neighbors) and SIMCA (Soft
Independent Modeling of Class Analogy),
two
established chemometric methods of
Pattern Recognition, have been used for
modeling. A model for the
active and inactive compounds was
created and
validated using 26 samples as
training set and a set of 16 1,4-naphthoquinone
derivatives was used as a
test to predict their activity/inactivity.
Lec23