Metabolic-Hydroxy and Carboxy Functionalization of Alkyl Moieties in Drug Molecules: Prediction of Structure Influence and Pharmacologic Activity
Total Page：16
File Type：pdf, Size：1020Kb
molecules Review Metabolic-Hydroxy and Carboxy Functionalization of Alkyl Moieties in Drug Molecules: Prediction of Structure Influence and Pharmacologic Activity Babiker M. El-Haj 1,* and Samrein B.M. Ahmed 2 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, University of Science and Technology of Fujairah, Fufairah 00971, UAE 2 College of Medicine, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 00971, UAE; [email protected] * Correspondence: [email protected] Received: 6 February 2020; Accepted: 7 April 2020; Published: 22 April 2020 Abstract: Alkyl moieties—open chain or cyclic, linear, or branched—are common in drug molecules. The hydrophobicity of alkyl moieties in drug molecules is modified by metabolic hydroxy functionalization via free-radical intermediates to give primary, secondary, or tertiary alcohols depending on the class of the substrate carbon. The hydroxymethyl groups resulting from the functionalization of methyl groups are mostly oxidized further to carboxyl groups to give carboxy metabolites. As observed from the surveyed cases in this review, hydroxy functionalization leads to loss, attenuation, or retention of pharmacologic activity with respect to the parent drug. On the other hand, carboxy functionalization leads to a loss of activity with the exception of only a few cases in which activity is retained. The exceptions are those groups in which the carboxy functionalization occurs at a position distant from a well-defined primary pharmacophore. Some hydroxy metabolites, which are equiactive with their parent drugs, have been developed into ester prodrugs while carboxy metabolites, which are equiactive to their parent drugs, have been developed into drugs as per se. In this review, we present and discuss the above state of affairs for a variety of drug classes, using selected drug members to show the effect on pharmacologic activity as well as dependence of the metabolic change on drug molecular structure. The review provides a basis for informed predictions of (i) structural features required for metabolic hydroxy and carboxy functionalization of alkyl moieties in existing or planned small drug molecules, and (ii) pharmacologic activity of the metabolites resulting from hydroxy and/or carboxy functionalization of alkyl moieties. Keywords: alkyl moieties; hydroxy functionalization; carboxy functionalization; prodrug metabolic activation; primary and auxiliary pharmacophores; auxophores 1. Introduction Nonpolar alkyl moieties are frequently incorporated into drug molecules to serve pharmacodynamic and/or pharmacokinetic purposes. Being lipophilic, alkyl moieties are metabolized in phase I via hydroxy functionalization to alcohols—a process which is, in some cases, followed by carboxy functionalization. Usually, the carboxyl and sterically unhindered hydroxyl groups in the resulting metabolites are conjugated in phase II by glucuronic acid. The chemical forms and metabolic products of the alkyl moieties surveyed in this review are summarized in Table1. Molecules 2020, 25, 1937; doi:10.3390/molecules25081937 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 29 Table 1. Moieties metabolized by hydroxy and carboxy functionalization. Aliphatic moieties metabolized by oxidative Molecules 2020, 25, 1937 Metabolic products 2 of 29 hydroxylation Primary, secondary, or tertiary alcohols, Table 1. Moieties metabolized by hydroxydepending and carboxy on functionalization. the class of substrate carbon; Alkyl (linear or branched) primary alcohols are further oxidized to Aliphatic Moieties Metabolized by Metabolic Products Oxidative Hydroxylation carboxylic acids Unhindered methylene groups in alicycles and Primary, secondary, or tertiary alcohols, depending on the aliphatic Alkylheterocycles (linear or (usually branched) at the farthest class of substrate carbon;Secondary primary alcohols alcohols are further position from the monosubstituent) oxidized to carboxylic acids Unhindered methylene groups in alicycles and Primary alcohols, followed by oxidation to Benzylic methyl groups aliphatic heterocycles (usually at the farthest Secondarycarboxyl alcohols group position from the monosubstituent) Methyl groups bonded to alicycles or Primary alcohols, followed by oxidation to Benzylicheterocycles methyl groups Primary alcohols, followedcarboxyl by oxidation groups to carboxyl group MethylMethylene groups groups bonded alpha to alicycles to both or heterocycles carbonyl and Primary alcohols, followed by oxidation to carboxyl groups Secondary alcohols Methylene groups alpha to both carbonyl and imino groups Secondary alcohols imino groups Secondary alcohol; usually followed by Secondary alcohol; usually followed by carbonyl compound CarbonsCarbons α toto a a heteroatom heteroatom in ain heterocycle a heterocycle carbonyl compound (aldehyde or ketone) (aldehyde or ketone) elimination elimination Primary alcohols in open-chain alkyls and secondary Allylic carbons Primary alcohols in open-chain alkyls and Allylic carbons alcohols in alicycles secondary alcohols in alicycles Generally, alkylsalkyls are found in drug molecules in their capacity as functional groups or as frameworks for (or carriers of) hydrophilic or other hydrophobic functional groups. Usually, Usually, internal ! linear alkyls assume the role of frameworks,frameworks, while ω methyls of terminal linear or branched alkyls assume primary or auxiliary pharmacophoric roles by interacting with biological targets through van der Waals binding.binding. In In addition, internal internal linear linear alkyls alkyls may be used as spacers between functional groups for didifferentfferent purposes—mainlypurposes—mainly toto extendextend thethe chainchain for for one one of of the the functional functional groups groups to to reach reach a abinding binding site. site. Further, Further branching, branching of of alkyl alkyl chains chains results resultsin incompactness: compactness: thisthis feature will cause less disruption of the hydrogen-bondinghydrogen-bonding network of water. Consequently, the lipophilicity of the drug containing the branchedbranched alkylalkyl groupgroup willwill decrease, decrease, and and if if the the drug’s drug’s mechanism mechanism of of action action is relatedis related to toits its lipophilicity, lipophilicity, then then a significant a significant alteration alteration in thein the biologic biologic eff ecteffect will will ensue ensue [1]. [1]. CCycloalkylycloalkyl groupsgroups encountered encountered in drugin drug molecules molecules mostly mostly extend fromexten cyclopropyld from cyclopropyl to cyclohexyl. to cyclohexylIn drug design,. In drug cycloalkyl design, cycloalkyl groups are groups substituted are substituted for open-chain for open alkyl-chain groups alkyl gr tooups (i) betterto (i) better fill a fillhydrophobic a hydrophobic pocket inpocket a receptor, in a andreceptor (ii) introduce, and (ii) rigidity introduce and limitrigidity the numberand limit of conformationsthe number of a conformationsdrug molecule maya drug adopt. molecule Both emayffects adopt. contribute Both to effects attaining contribute more drug to attain affinitying and more selectivity drug affinity of the anddrug se containinglectivity of such the drug groups containing [2–4]. In monosubstitutedsuch groups [2–4] cyclohexyl. In monosubstituted groups—the cyclohexyl most common groups in— drugthe mostmolecules—metabolic common in drug hydroxylation molecules— ismetabolic stereoselective, hydroxylation favoring is the stereoselective,trans isomer for favoring its higher the stability trans withisomer respect for its to higher the cis stabilityisomer (Figurewith respect1)[5]. to the cis isomer (Figure 1) [5]. Monosubstituted R cyclohexane 4-Hydroxylation 3-Hydroxylation H OH 4 OH 4 H R + R R H + R OH 3 3 H H H OH H H trans-4-hydroxy cis-4-hydroxy trans-3-hydroxy cis-3-hydroxy Figure 1. Stereoselective metabolic oxidation of monosubstituted cyclohexyl moiety. Mechanism of Metabolic Oxidation of Alkyl Moieties Metabolic hydroxylation of alkyl groups is catalyzed by a family of monooxygenase enzymes, known as the “cytochrome P450” family, that contain heme redox centers. The heme group is Molecules 2020, 25, x FOR PEER REVIEW 3 of 29 Figure 1. Stereoselective metabolic oxidation of monosubstituted cyclohexyl moiety. 1.1. Mechanism of Metabolic Oxidation of Alkyl Moieties Molecules 2020, 25, 1937 3 of 29 Metabolic hydroxylation of alkyl groups is catalyzed by a family of monooxygenase enzymes, known as the “cytochrome P450” family, that contain heme redox centers. The heme group is characterizedcharacterized by an an iron iron atom atom coordinated coordinated to tothe the nitrogen nitrogen atoms atoms of four of four linked linked pyrrole pyrrole rings. rings. The Themechanism mechanism of metabolic of metabolic hydroxylation hydroxylation involves involves free free-radical-radical formation formation at the at thesubstrate substrate carbon carbon in the in thealkyl alkyl moiety, moiety, as asillustrated illustrated in inFigure Figure 22 [6[ –610–10]. ].In In drug drug molecules molecules containing containing more more than than one classclass ofof carboncarbon atoms,atoms, thethe prioritypriority ofof metabolicmetabolic hydroxylationhydroxylation isis dictateddictated byby thethe stabilitystability ofof thethe intermediateintermediate freefree radicals;radicals; however, however, anomalies anomalies may may occur occur due todue prevailing to prevailing electronic electronic