Novel Alkylating Derivatives of Chloramphenicol Suitable for Topical Treatment of Dermal Neoplasms

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.
Place and 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 pharmacological properties 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. Evaluation of 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 to have 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 rates of 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.