Novel Alkylating Derivatives of Chloramphenicol Suitable for Topical Treatment of Dermal Neoplasms| Chapter: 3 | Modern Advances in Pharmaceutical Research Vol. 1
Aims: To evaluate
the efficacy of two alkylating structural analogues of chloramphenicol that
have potential for application for treatment of dermal sited neoplasms.
Study Design: Two
compounds have been shown to alkylate guanosine-5’-diphosphate (GDP) at
physiological conditions. These same compounds are evaluated for dermal
penetration based on Kp and compared to other alkylating agents applied for
treatment of skin cancer.
Placeand
Duration of Study: University of Nebraska, Omaha Nebraska
from December 2013 to May 2014 and March to August of 2002.
Methodology: Two analogues of chloramphenicol were
synthesized and shown to alkylate GDP at pH
7.4 and 37ºC.
Various
pharmacologicalproperties of these
two analogues, such
as Log P, molecular weight, polar surface area, etc,
were determined and compared. The dermal
permeability coefficient Kp was
determined for two
analogues based on
their molecular weight
and partition coefficient Log P.
The numerical values of Kp were used to prediction of the distance each
analogue is expected to travel in penetration of a dermal barrier. Result was
plotted and compared to the anticancer agent’s carmustine, mustargen, and
5-fluorouracil. Evaluationof the analogues included findings of previous
studies.
Results: Two analogues of chloramphenicol alkylate sites on
GDP. The properties of compound 1 and compound 2 were determined and when
compared to the parent structure chloramphenicol were found tohave
favorable drug likeness.
Values of Log P and
permeability coefficient Kp for
compounds 1 and 2 are; 3.343, 3.312, 0.00244 cm/hour, 0.000768 cm/hour,
respectively. Values of Kp for both
compound 1 and 2 were greater than that of chloramphenicol at 0.000131 cm/hour.
Plots of skin penetration showed compounds 1 and 2 to be superior to 5-fluorouracil.
Conclusion: Analogues 1 and 2 were shown to have alkylation
activity and properties suitable for drug likeness. Both compounds have high
penetration ratesof dermal layers. The pharmaceutical properties of two structural
analogues of the
antibiotic chloramphenicol were
determined and analyzed for
potential of topical administration. Compound 1 and compound 2 were both shown
in previous studies to
alkylate
guanosine-5’-diphosphate,
amino acids, and
p-chloroaniline. Both
analogues 1 and 2 possess
alkyl chloride substituents
in place of
hydroxyl groups found
on chloramphenicol. Dermal permeability coefficient Kp of analogue 1
(0.00244 cm/hour) is greater than Kp for carmustine, Mustargen, and
5-fluorouracil. Analogue 2 value of Kp
(0.000768 cm/hour) is greater than Kp for anticancer drug 5-fluorouracil. The diffusion coefficient D for analogue 1
and 2 are competitive with those of carmustine, Mustargen, and 5-fluorouracil.
Aqueous solubility of analogues 1 and 2 are considerably lower than for
chloramphenicol, which is consistent with the much larger Log P values for 1
and 2. Plots of distance traveled, based on their values of Kp, showed that
compound 1 moves further than carmustine, Mustargen, and 5-fluorouracil.
Compound 2 still travels further than chloramphenicol and anticancer agent
5-fluorouracil. These results strongly support the potential of compound 1 and
2 as effective topical agents in treatment of skin neoplasms and mycosis
fungoides.
Biography of author(s)
Ronald Bartzatt
University of Nebraska, Durham Science Center, Department of
Chemistry, 6001 Dodge Street, Omaha, NE 68182, USA.
Read full article: http://bp.bookpi.org/index.php/bpi/catalog/view/47/231/396-1
View volume: https://doi.org/10.9734/bpi/mapr/v1
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