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Review
. 2015 Dec 29;21(1):42.
doi: 10.3390/molecules21010042.

The Prodrug Approach: A Successful Tool for Improving Drug Solubility

Daniela Hartmann Jornada  1 , Guilherme Felipe dos Santos Fernandes  2 , Diego Eidy Chiba  3 , Thais Regina Ferreira de Melo  4 , Jean Leandro dos Santos  5 , Man Chin Chung  6
Affiliations
Review

The Prodrug Approach: A Successful Tool for Improving Drug Solubility

Daniela Hartmann Jornada et al. Molecules. .

Abstract

Prodrug design is a widely known molecular modification strategy that aims to optimize the physicochemical and pharmacological properties of drugs to improve their solubility and pharmacokinetic features and decrease their toxicity. A lack of solubility is one of the main obstacles to drug development. This review aims to describe recent advances in the improvement of solubility via the prodrug approach. The main chemical carriers and examples of successful strategies will be discussed, highlighting the advances of this field in the last ten years.

Keywords: molecular modification; prodrug; solubility; solubility of prodrugs; water-soluble prodrugs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
In vivo bioactivation of prodrugs by enzymatic and/or chemical transformations.
Figure 2
Figure 2
Glycyl ester and amino-acid-ester prodrugs [19,20].
Figure 3
Figure 3
Bicyclic furanopyrimidine nucleoside analogue [25].
Figure 4
Figure 4
Ethylene glycol and propylene glycol prodrugs of oleanoic acid [29,30].
Figure 5
Figure 5
PEG prodrugs of oridonin [33].
Figure 6
Figure 6
General structure of gambogic-acid PEG prodrugs [35].
Figure 7
Figure 7
Taxoid prodrugs [37,38].
Figure 8
Figure 8
Paclitaxel-disulfide prodrug with anticancer activity [41].
Figure 9
Figure 9
Etoposide ester prodrugs containing malic acid [42].
Figure 10
Figure 10
NSAID ester prodrugs [45,46].
Figure 11
Figure 11
Prodrugs of quercetin and γ-T3 [48,59].
Figure 12
Figure 12
N-acyloxymethyl ester prodrug [60].
Figure 13
Figure 13
Peptide prodrugs of acyclovir and SB-3CT [62,64].
Figure 14
Figure 14
Prodrug derivative of DW2282 [66].
Figure 15
Figure 15
Dendritic naproxen-peptides prodrugs [72].
Figure 16
Figure 16
Benzamide and carboxamide prodrugs of PC190723 [73,74].
Figure 17
Figure 17
Glucuronide and pyrazolo[3,4-d]pyrimides prodrugs [77,78].
Figure 18
Figure 18
Photopaclitaxel prodrug [82].
Figure 19
Figure 19
CHS8281 prodrug [83].
Figure 20
Figure 20
Copolymer-paclitaxel conjugate [84].
Figure 21
Figure 21
Prodrug release based on an enzymatic cleavage followed by a 1,6-elimination reaction [88].
Figure 22
Figure 22
Cadalene prodrug with improved solubility in water [90].
Figure 23
Figure 23
(a) Amphotericin B and nystatin prodrugs; (b) Bisphosphonate doxorubicin prodrug [91,92].
Figure 24
Figure 24
Paclitaxel-biopolymer-conjugated prodrug [93].
Figure 25
Figure 25
Structures of the prodrugs of lopinavir and ritonavir [99].
Figure 26
Figure 26
Benzimidazole phosphate prodrug [100].
Figure 27
Figure 27
Chalcone-phosphate prodrugs [102].
Figure 28
Figure 28
Propofol prodrug [103].
Figure 29
Figure 29
SB-3CT prodrug and its active metabolite [104].
Figure 30
Figure 30
Benzimidazole and SNS-314 phosphate prodrugs [107,108].
Figure 31
Figure 31
Carbamazepine and PC407 prodrugs [111,112].
Figure 32
Figure 32
Tetrahydrocurcumin and famotidine prodrugs [116,118].
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