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. 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 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.

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