Chiral Alkyl Halides: Underexplored Motifs in Medicine

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Nov 4, 2016 - used in medicine since the mid-1800s [12], however their mechanism ... One protein that halogenated anesthetics have been shown to interact ...

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Chiral Alkyl Halides: Underexplored Motifs in Medicine Bálint Gál, Cyril Bucher and Noah Z. Burns * Department of Chemistry, Stanford University, 333 Campus Drive, Stanford, CA 94305, USA; [email protected] (B.G.); [email protected] (C.B.) * Correspondence: [email protected]; Tel.: +1-650-723-2961 Academic Editor: Miguel O. Mitchell Received: 24 September 2016; Accepted: 31 October 2016; Published: 4 November 2016

Abstract: While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems. A number of chlorinated compounds in the pharmaceutical and food industries, as well as a growing number of halogenated marine natural products showing unique bioactivity, illustrate the role that chiral alkyl halides can play in drug discovery. Through a series of case studies, we demonstrate in this review that these motifs can indeed be stable under physiological conditions, and that halogenation can enhance bioactivity through both steric and electronic effects. Our hope is that, by placing such compounds in the minds of the chemical community, they may gain more traction in drug discovery and inspire more synthetic chemists to develop methods for selective halogenation. Keywords: alkyl halide; stereochemistry; lipophilicity; anesthetic; clindamycin; corticosteroid; pimecrolimus; sucralose; halomon; lapachone; astins; forazoline

1. Introduction Alkyl halides are among the most versatile compounds in the chemical industry. Small haloalkanes are some of the most commonly used solvents in chemical laboratories; chlorofluorocarbons have seen widespread use as refrigerants and propellants; and compounds containing both Br and F are often used in fire retardants. Within synthetic organic chemistry, they are commonly used in alkylation reactions, radical cascades, and alkyl cross-coupling chemistry [1–3]. The reactive nature of primary alkyl chlorides is sometimes exploited in medicinal chemistry and chemical biology. HaloTag is a modified haloalkane dehalogenase that is used to covalently bind to a synthetic ligand of choice and fuse to a protein of interest (Figure 1) [4]. This construct allows for a variety of experiments including protein purification, protein stability studies and protein translocation assays. This technology relies on the use of an alkyl chloride linker that rapidly (typically within minutes) forms a covalent bond with the protein tag under physiological conditions. Phenoxybenzamine, an irreversible α-blocker, forms covalent bonds with adrenergic receptors through the attack of a cysteine residue at the alkyl chloride moiety in transmembrane helix 3 (Figure 1) [5]. While primary alkyl halides are often reactive for displacement by nucleophiles, secondary and tertiary chlorides and bromides are significantly less reactive. As a testament to their stability, six drugs on the World Health Organization’s essential medicines list contain such motifs [6].

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  Figure 1. The structures of HaloTag and Phenoxybenzamine. 


A key consideration in drug development is the pharmacokinetic profile and efficacy of a drug  Figure 1. The structures of HaloTag and Phenoxybenzamine.  Figure 1. The structures of HaloTag and Phenoxybenzamine. candidate [7]. Halogenation of sp2 carbons is commonly used to increase lipophilicity, which can lead  A key consideration in drug development is the pharmacokinetic profile and efficacy of a drug  to  improved  membrane  permeability  and  oral isabsorption  [8].  Furthermore,  halogenation  also  A key consideration in drug development the pharmacokinetic profile and efficacy ofcan  a drug 2 carbons is commonly used to increase lipophilicity, which can lead  candidate [7]. Halogenation of sp enhance the blood–brain barrier permeability, which is crucial for drugs targeting the central nervous  2 candidate [7]. Halogenation of sp carbons is commonly used to increase lipophilicity, which can lead to  improved  membrane  permeability  and  oral  absorption  [8].  Furthermore,  halogenation  can  also  system [9]. These properties are most often exploited by the introduction of aryl chlorides into drug  to improved membrane permeability and oral absorption [8]. Furthermore, halogenation can also enhance the blood–brain barrier permeability, which is crucial for drugs targeting the central nervous  candidates [10]. Indeed, approximately a third of the compounds in clinical trials contain these motifs.  enhance the blood–brain barrier permeability, which is crucial for drugs targeting the central nervous system [9]. These properties are most often exploited by the introduction of aryl chlorides into drug  Intriguingly, alkyl chlorides are only used in a handful of drugs, some of which are described below.  system [9]. These properties are most often exploited by the introduction of aryl chlorides into drug candidates [10]. Indeed, approximately a third of the compounds in clinical trials contain these motifs.  This review aims to detail some compounds of medicinal significance that contain a halogen‐ candidates [10]. Indeed, approximately a third of the compounds in clinical trials contain these motifs. Intriguingly, alkyl chlorides are only used in a handful of drugs, some of which are described below.  bearing stereogenic center. We hope to illustrate the importance of these motifs and the roles they  Intriguingly, alkyl chlorides are only used in a handful of drugs, some of which are described below. This review aims to detail some compounds of medicinal significance that contain a halogen‐ play to enhance the biological and pharmacological properties of drugs. Fluorine, due to its small  This review aims to detail some compounds of medicinal significance that contain a halogen-bearing bearing stereogenic center. We hope to illustrate the importance of these motifs and the roles they  size and high electronegativity, imparts properties on molecules that are unique to this element. As  stereogenic center. We hope to illustrate the importance of these motifs and the roles they play to play to enhance the biological and pharmacological properties of drugs. Fluorine, due to its small  these  effects  have  been  reviewed  previously  [11],  herein  we  will  focus due on  alkyl  chlorides  and  enhance the biological and pharmacological properties of drugs. Fluorine, to its small size and size and high electronegativity, imparts properties on molecules that are unique to this element. As  bromides.  high electronegativity, imparts properties on molecules that are unique to this element. As these effects these  effects  have  been  reviewed  previously  [11],  herein  we  will  focus  on  alkyl  chlorides  and  have been reviewed previously [11], herein we will focus on alkyl chlorides and bromides. bromides.  2. Alkyl Halides in Medicine  2. Alkyl Halides in Medicine 2. Alkyl Halides in Medicine  2.1. Anesthetics  2.1. Anesthetics General anesthetics are agents that can cause reversible loss of consciousness. They have been  2.1. Anesthetics  anesthetics aremid‐1800s  agents that[12],  can however  cause reversible loss of consciousness. They have been used General in  medicine  since  the  their  mechanism  of  action  remains  a  topic  of  General anesthetics are agents that can cause reversible loss of consciousness. They have been  used in medicine since the mid-1800s [12], however their mechanism of action remains a topic of debate. For decades, the general view was that anesthetics act by nonspecific perturbation of lipid  used  in For medicine  since  mid‐1800s  [12], that however  their  mechanism  of  action  remains  a  topic  of  debate. decades, thethe  general view was anesthetics act by nonspecific perturbation of lipid membranes. This hypothesis has more recently been disproven as a result of a number of findings.  debate. For decades, the general view was that anesthetics act by nonspecific perturbation of lipid  membranes. This hypothesis has more recently been disproven as a result of a number of findings. Most Most  importantly,  stereospecific  effects  have  been  observed  for  general  anesthetic  binding.  Two  membranes. This hypothesis has more recently been disproven as a result of a number of findings.  importantly, stereospecific effects have been observed for general anesthetic binding. Two chiral alkyl chiral alkyl halide anesthetics, isoflurane and halothane, are on the WHO’s list of essential medicines  Most  importantly,  stereospecific  effects  have  for ofgeneral  halide anesthetics, isoflurane and halothane, are been  on theobserved  WHO’s list essentialanesthetic  medicinesbinding.  (Figure 2)Two  [6]. (Figure 2) [6].  chiral alkyl halide anesthetics, isoflurane and halothane, are on the WHO’s list of essential medicines  (Figure 2) [6]. 

  Figure 2. The structures of halothane and isoflurane.  Figure 2. The structures of halothane and isoflurane.


In 1991, N. P. Franks and W. R. Lieb found that the two optical isomers of isoflurane exhibited  Figure 2. The structures of halothane and isoflurane.  In 1991, N. P. Franks and W. R. Lieb found that the two optical isomers of isoflurane differential binding to ion channels in identified molluscan central nervous system neurons [13]. The  exhibited differential binding to ion channels in identified molluscan central nervous system In 1991, N. P. Franks and W. R. Lieb found that the two optical isomers of isoflurane exhibited  (+)‐isomer was roughly twofold more effective than the (−)‐isomer at eliciting the anesthetic‐activated  neurons [13]. The (+)-isomer was roughly twofold more effective than the (−)-isomer at eliciting differential binding to ion channels in identified molluscan central nervous system neurons [13]. The  potassium current IK(An) at the human median effect dose (ED50) for general anesthesia. Both isomers  the anesthetic-activated potassium current IK(An) at the human median effect dose (ED50 ) for general (+)‐isomer was roughly twofold more effective than the (−)‐isomer at eliciting the anesthetic‐activated  were found to be equally effective at disrupting lipid bilayers.  anesthesia. Both isomers were found to be equally effective at disrupting lipid bilayers. potassium current I K(An) at the human median effect dose (ED 50) for general anesthesia. Both isomers  It  is  now  postulated  that  general  anesthetics  exert  their  action  through  the  activation  of  It is now postulated that general anesthetics exert their action through the activation of inhibitory were found to be equally effective at disrupting lipid bilayers.  inhibitory central nervous system (CNS) receptors, and through the inactivation of CNS excitatory  central nervous system (CNS) receptors, and through the inactivation of CNS excitatory receptors [12]. It  is  now  postulated  that  general  anesthetics  exert  their  action  through  the  activation  of  receptors [12]. Recently, a small number of molecular targets have emerged. These include gamma‐ Recently, a small number of molecular targets have emerged. These include gamma-aminobutyric acid inhibitory central nervous system (CNS) receptors, and through the inactivation of CNS excitatory  aminobutyric acid type A receptors (GABAA), two pore domain potassium (2PK) channels, and N‐ type A receptors (GABAA ), two pore domain potassium (2PK) channels, and N-methyl-D-aspartate receptors [12]. Recently, a small number of molecular targets have emerged. These include gamma‐ methyl‐D‐aspartate (NMDA) receptors. How anesthetics interact with these targets on a molecular  (NMDA) receptors. How anesthetics interact with these targets on a molecular level is also aminobutyric acid type A receptors (GABAA), two pore domain potassium (2PK) channels, and N‐ level is also becoming clearer.  becoming clearer. methyl‐D‐aspartate (NMDA) receptors. How anesthetics interact with these targets on a molecular  level is also becoming clearer. 

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One protein that halogenated anesthetics have been shown to interact with is ferritin, a large 4-helix One protein that halogenated anesthetics have been shown to interact with is ferritin, a large 4‐ bundle protein. In 2005, Liu and coworkers solved the structure of both halothane/ferritin One protein that halogenated anesthetics have been shown to interact with is ferritin, a large 4‐ helix bundle protein. In 2005, Liu and coworkers solved the structure of both halothane/ferritin and  and isoflurane/ferritin complexes (Figure 3) [14]. Halothane binds in a hydrophobic cavity between helix bundle protein. In 2005, Liu and coworkers solved the structure of both halothane/ferritin and  isoflurane/ferritin complexes (Figure 3) [14]. Halothane binds in a hydrophobic cavity between two  two ferritin monomers. While racemic compound was used for this study, the electron density map isoflurane/ferritin complexes (Figure 3) [14]. Halothane binds in a hydrophobic cavity between two  ferritin  monomers.  While  compound  was  used  for this  this  study, the  the  electron  density  map  ferritin  monomers.  While racemic  racemic  compound  was  used  study,  electron  density  map  revealed that the (+)-isomer was twice as abundant as for  the (−)-isomer. Due to the hydrophobic revealed  that  the  (+)‐isomer  was  twice  as  abundant  as  the  (−)‐isomer.  Due  to  the  hydrophobic  revealed  that  the  (+)‐isomer  was  twice  as  abundant  as  the  (−)‐isomer.  Due  to  the  hydrophobic  environment, the strongest contributors to binding are halogen bonding interactions [15] between environment, the strongest contributors to binding are halogen bonding interactions [15] between the  the Brenvironment, the strongest contributors to binding are halogen bonding interactions [15] between the  of halothane and ferritin’s carbonyl oxygen at Leu24, as well as a halogen-π contact between Br Br  of of  halothane  and  ferritin’s  Leu24, as  as well  well as  as a a halogen‐π  halogen‐π  contact  between  halothane  and  ferritin’s carbonyl  carbonyl oxygen  oxygen  at  Leu24,  contact  between  halothane’s Cl atom and the aromatic ring in Tyr28 [16], Figure 3. These results very clearly illustrate halothane’s Cl atom and the aromatic ring in Tyr28 [16], Figure 3. These results very clearly illustrate  halothane’s Cl atom and the aromatic ring in Tyr28 [16], Figure 3. These results very clearly illustrate  that the stereochemistry of alkyl halides matters for binding interactions, and that halogen atoms can that the stereochemistry of alkyl halides matters for binding interactions, and that halogen atoms can  that the stereochemistry of alkyl halides matters for binding interactions, and that halogen atoms can  provide key binding interactions. provide key binding interactions.  provide key binding interactions. 


  Figure 3. Complex of halothane with apoferritin. The key binding interactions include halogen bonds 

Figure 3. Complex of halothane with apoferritin. The key binding interactions include halogen bonds between Br and the carbonyl oxygen of Leu24, and Cl‐π interaction between Cl and Tyr28.  Figure 3. Complex of halothane with apoferritin. The key binding interactions include halogen bonds  between Br and the carbonyl oxygen of Leu24, and Cl-π interaction between Cl and Tyr28. between Br and the carbonyl oxygen of Leu24, and Cl‐π interaction between Cl and Tyr28.  2.2. Clindamycin Clindamycin  Clindamycin Clindamycin is a broad spectrum antibiotic derived semisynthetically from the natural product  lincomycin  (Figure  4).  Clindamycin  is  used  for derived the  treatment  of  a  variety  of  bacterial  infections,  Clindamycin is a broad spectrum antibiotic semisynthetically from the natural product Clindamycin is a broad spectrum antibiotic derived semisynthetically from the natural product  including  bone  and  joint  infections,  strep  throat,  pneumonia,  and  endocarditis  [17].  Similarly  to  lincomycin (Figure 4). Clindamycin is used for the of a variety of bacterial infections, including lincomycin  (Figure  4).  Clindamycin  is  used  for treatment the  treatment  of  a  variety  of  bacterial  infections,  macrolide  antibiotics,  lincomycin  and  clindamycin  inhibit  protein  synthesis  by  ribosomal  bone and jointbone  infections, strepinfections,  throat, pneumonia, and endocarditis to macrolide antibiotics, including  and  joint  strep  throat,  pneumonia, [17]. and Similarly endocarditis  [17].  Similarly  to  translocation—they bind to the 50S rRNA of the large bacterial ribosome subunit [18].  lincomycin and clindamycin inhibit protein by ribosomal translocation—they bind to the 50S macrolide  antibiotics,  lincomycin  and  synthesis clindamycin  inhibit  protein  synthesis  by  ribosomal  rRNA of the large bacterial ribosome subunit [18]. translocation—they bind to the 50S rRNA of the large bacterial ribosome subunit [18]. 

  Figure 4. The structures of lincomycin and clindamycin. 

  Figure 4. The structures of lincomycin and clindamycin.  Figure 4. The structures of lincomycin and clindamycin.

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In 1985, Francois Le Goffic investigated structure-activity relationships of lincomycin analogs [19]. TheyMar. Drugs 2016, 14, 206  found that clindamycin is highly active compared to lincomycin against a number of test 4 of 11  organisms, while having lower toxicity levels. A number of derivatives at the 7 position have been In 1985, Francois Le Goffic investigated structure‐activity relationships of lincomycin analogs  synthesized and tested (see Table 1). The results indicate that in vivo potency is increased when the [19]. They found that clindamycin is highly active compared to lincomycin against a number of test  hydrophilic hydroxyl groups are substituted with chloride or bromide. When the stereochemistry of organisms, while having lower toxicity levels. A number of derivatives at the 7 position have been  C7 is swapped, the efficacy is increased. This clearly shows the importance of the stereochemistry synthesized and tested (see Table 1). The results indicate that in vivo potency is increased when the  of chiral alkyl halides for biological activity. Interestingly, substituting chlorides with bromides and hydrophilic hydroxyl groups are substituted with chloride or bromide. When the stereochemistry of  iodides further increased activity. These results clearly demonstrate that halogenation can enhance C7 is swapped, the efficacy is increased. This clearly shows the importance of the stereochemistry of  efficacy in alkyl  vivo,halides  and that exact stereochemistry can play an important rolewith  for bioactivity. chiral  for the biological  activity.  Interestingly,  substituting  chlorides  bromides  and  iodides further increased activity. These results clearly demonstrate that halogenation can enhance  Table 1. Modification of lincomycin at the C-7 site. All results are MIC (mg/L). efficacy in vivo, and that the exact stereochemistry can play an important role for bioactivity.  Compound Straph. aureus Str. faecalis Table 1. Modification of lincomycin at the C‐7 site. All results are MIC (mg/L).  R1 = Compound  OH, R2 = H R1 R=1 = OH, R H, R2 = OH 2 = H  R1 = Cl, R2 = H R1 = H, R2 = OH  R1 = H, R2 = Cl R1 = Cl, R2 = H  R1 = H, R2 = Br R R1 =1 = H, R H, R2 2= = Cl  I R1 = H, R2 = Br  R1 = H, R2 = I 

0.4 Straph. aureus  0.4 1.6 0.8 1.6  0.1 0.8  0.05 0.1 0.05 0.05  0.05 

12.5 Str. faecalis  12.5  25 12.5 25  6.2 12.5  6.2 6.2  3.2 6.2  3.2   

To better understand these differences between lincomycin and clindamycin on a molecular To  better  understand  these  differences  between  lincomycin  and  clindamycin  on  a the molecular  level, further studies were conducted to elucidate the binding properties. In 1992, interaction level, further studies were conducted to elucidate the binding properties. In 1992, the interaction of  of clindamycin and lincomycin with E. coli 23S ribosomal RNA was investigated by chemical clindamycin  with  E. affinities coli  23S  of ribosomal  by were chemical  footprinting [20].and  Thelincomycin  in vitro binding the twoRNA  drugswas  for investigated  the ribosome found to footprinting [20]. The in vitro binding affinities of the two drugs for the ribosome were found to be  be roughly the same (Kdiss = 5 µM for lincomycin and 8 µM for clindamycin), even though the exact roughly  the  same  (Kdiss  =  5  μM  for  lincomycin  and  8  μM  for  clindamycin),  even  though  the  exact  geometries of binding were somewhat different. The structure of a complex between clindamycin and geometries of binding were somewhat different. The structure of a complex between clindamycin  the 50S ribosomal subunit of the eubacterium Deinococcus radidurans was solved in 2001 (Figure 5) [21]. and the 50S ribosomal subunit of the eubacterium Deinococcus radidurans was solved in 2001 (Figure  The crystal structure revealed no strong interaction with the Cl atom of clindamycin. Instead, the key 5) [21]. The crystal structure revealed no strong interaction with the Cl atom of clindamycin. Instead,  binding interactions arise from hydrogen bonding interactions between the hydroxyl groups of the the key binding interactions arise from hydrogen bonding interactions between the hydroxyl groups  sugarof moiety and nucleosides. Both of these concluded that the higher of clindamycin the  sugar  moiety  and  nucleosides.  Both studies of  these  studies  concluded  that  the activity higher  activity  of  was to not  attributable  to  stronger  binding,  but  to  increased  lipophilicity.  However, alone was clindamycin  not attributable stronger binding, but to increased lipophilicity. However, lipophilicity lipophilicity  alone  cannot  explain  the  activity  of  C7  stereoisomers.  Further  research  in cannot explain the differential activity ofdifferential  C7 stereoisomers. Further research would be instructive would be instructive in elucidating how the chloride stereochemistry exactly bears on bioactivity.  elucidating how the chloride stereochemistry exactly bears on bioactivity.

  Figure 5. Crystal structure of clindamycin bound to the peptidyl transferase cavity of the 50S subunit.  Figure 5. Crystal structure of clindamycin bound to the peptidyl transferase cavity of the 50S subunit. The key binding interactions are provided by the sugar hydroxyl groups.  The key binding interactions are provided by the sugar hydroxyl groups.

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5 of 11 Corticosteroids  Corticosteroids 2.3. Corticosteroids  Corticosteroids are among the most widely used drug classes due to their ability to exert Corticosteroids are among the most widely used drug classes due to their ability to exert intense  intense biological effects in almost any(Figure  organ 6).  (Figure 6). often  Theythe  aredrug  oftenof the drug choice biological  effects  in  almost  any  organ  They  are  choice  for oftheir  anti‐for Corticosteroids are among the most widely used drug classes due to their ability to exert intense  their anti-inflammatory and immunosuppressive [22].the  These actfor  by binding inflammatory  and  immunosuppressive  properties  These  steroids  act  by  binding  to to biological  effects  in  almost  any  organ  (Figure  6).  properties They [22].  are  often  drug steroids of  choice  their  anti‐ glucocorticoid receptors (GRs), therefore the receptor-binding affinity is a major determinant glucocorticoid  receptors  (GRs),  therefore  the  receptor‐binding  affinity  is  a  major  determinant  of  inflammatory  and  immunosuppressive  properties  [22].  These  steroids  act  by  binding  to of therapeutic potential [23]. (GRs),  therefore  the  receptor‐binding  affinity  is  a  major  determinant  of  therapeutic potential [23].  glucocorticoid  receptors  therapeutic potential [23]. 

    Figure 6. The structures of chlorinated corticosteroids used in medicine.  Figure 6. The structures of chlorinated corticosteroids used in medicine. Figure 6. The structures of chlorinated corticosteroids used in medicine. 

In the case of mometasone furoate, it was found that there is a dipole–dipole interaction between  In the case of mometasone furoate, it was found that there is a dipole–dipole interaction between the C21 Cl and an asparagine residue in the binding pocket AncGR2‐Asn33 that contributes to the  In the case of mometasone furoate, it was found that there is a dipole–dipole interaction between  the C21 Cl and an asparagine residue in the binding pocket AncGR2-Asn33 that contributes to the high affinity of binding [24].  the C21 Cl and an asparagine residue in the binding pocket AncGR2‐Asn33 that contributes to the  high affinity of binding [24]. To correlate other structural features with binding affinity to glucocorticoid receptors, extensive  high affinity of binding [24].  To correlate other structuralstudies  features withcarried  binding affinity glucocorticoid receptors, structure  activity  relationship  were  out  on  this toclass  of  compounds  [25,26]. extensive A  key  To correlate other structural features with binding affinity to glucocorticoid receptors, extensive  structure activity relationship studies were carried out to  on 6–7‐fold  this classincrease  of compounds [25,26]. A key finding  was  that  fluorination  or  chlorination  leads  in  binding  affinity.  structure  activity  relationship  studies  were  carried  out  on  this  class  of  compounds  [25,26].  A  key  finding was that fluorination or chlorination leads to 6–7-fold increase in binding affinity. Interestingly, Interestingly,  at  the  positions leads  actually  implies  a  size  finding  was  bromination  that  fluorination  or same  chlorination  to  reduces  6–7‐fold binding,  increase which  in  binding  affinity.  bromination at the same positions actually binding, implies a sizewhich  limitation for effective limitation for effective fit in the binding pocket. The origin of these effects is unknown at this stage,  Interestingly,  bromination  at  the  same  reduces positions  actually which reduces  binding,  implies  a  size  fit further research is needed to understand how halogenation can have such a striking effect on binding  in the binding pocket. The origin of these effects is unknown at this stage, further research is needed limitation for effective fit in the binding pocket. The origin of these effects is unknown at this stage,  to affinity and in turn drug efficacy.  understand how halogenation can have such a striking effect on binding affinity and in turn further research is needed to understand how halogenation can have such a striking effect on binding  drug efficacy. affinity and in turn drug efficacy.  2.4. Pimecrolimus Pimecrolimus  Pimecrolimus Pimecrolimus and tacrolimus are immunosuppressants used for the topical treatment of atopic  Pimecrolimus and They  tacrolimus are immunosuppressants used for and  the topical of atopic dermatitis  (eczema).  both  bind  to  the  protein  macrophilin‐12  inhibit treatment the  phosphatase  Pimecrolimus and tacrolimus are immunosuppressants used for the topical treatment of atopic  calcineurin, resulting in the blockage of T cell activation (Figure 7) [27].  dermatitis (eczema). They both bind to the protein macrophilin-12 and inhibit the phosphatase dermatitis  (eczema).  They  both  bind  to  the  protein  macrophilin‐12  and  inhibit  the  phosphatase  calcineurin, resulting in the blockage of T cell activation (Figure 7) [27]. calcineurin, resulting in the blockage of T cell activation (Figure 7) [27]. 

Figure 7. The structures of Pimecrolimus and Tacrolimus.  Figure 7. The structures of Pimecrolimus and Tacrolimus.  Figure 7. The structures of Pimecrolimus and Tacrolimus.


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Despite  aa  high high  degree degree  of of similarity similarity  in in structure structure and and mechanism mechanism of of action, action, pimecrolimus pimecrolimus  and and  Despite tacrolimus display characteristic differences in terms of pharmacological profile [28]. As a result of  tacrolimus display characteristic differences in terms of pharmacological profile [28]. As a result OH  to to Cl Cl substitution,  the  of OH substitution,pimecrolimus  pimecrolimusis isapproximately  approximatelyeight  eighttimes  timesmore  more lipophilic  lipophilic based  based on  on the octanol/water  distribution    = =6.99  0.05  for  pimecrolimus  vs. vs. 6.09  ±  0.04  for  octanol/water distributioncoefficient  coefficient (ElogD (ElogDoctoct 6.99± ± 0.05 for pimecrolimus 6.09 ± 0.04 tacrolimus). Consequently, it has a higher affinity to the skin and lower levels of permeation. This  for tacrolimus). Consequently, it has a higher affinity to the skin and lower levels of permeation. explains  the  observed  lower  systemic  exposure  to to pimecrolimus  topical  This explains the observed lower systemic exposure pimecrolimusthan  thanto  totacrolimus  tacrolimus after  after topical application. The The unbound unbound  fraction  pimecrolimus  in  human  plasma  was  approximately  application. fraction of of  pimecrolimus in human plasma was approximately 9-fold 9‐fold  lower lower compared with that of tacrolimus (0.4 ± 0.1 vs. 3.7 ± 0.8%).  compared with that of tacrolimus (0.4% ± 0.1% vs. 3.7% ± 0.8%). 2.5. Sucralose 2.5. Sucralose  ® is one of the most common artificial sweeteners and sugar substitutes Sucralose Sucralose  (Splenda (Splenda®) ) is  one  of  the  most  common  artificial  sweeteners  and  sugar  substitutes  (Figure 8) [29]. The majority of ingested sucralose is not metabolized by the body, which makes it (Figure 8) [29]. The majority of ingested sucralose is not metabolized by the body, which makes it  safe and also noncaloric [30]. This example in particular emphasizes the metabolic stability of alkyl safe and also noncaloric [30]. This example in particular emphasizes the metabolic stability of alkyl  chlorides, when they are are  adjacent to other electron-withdrawing heteroatoms (even primary chlorides, especially especially  when  they  adjacent  to  other  electron‐withdrawing  heteroatoms  (even  halides can be stable). primary halides can be stable).  Researchers have been investigating the structural requirements for sweetness since the 1960s. Researchers have been investigating the structural requirements for sweetness since the 1960s.  While taste sensing is a complex phenomenon, some general rules have been established for which While taste sensing is a complex phenomenon, some general rules have been established for which  most sweet-tasting compounds adhere to. Schallenberger and Acree proposed that for a compound most sweet‐tasting compounds adhere to. Schallenberger and Acree proposed that for a compound  to be sweet, it needs to possess a hydrogen bond donor, and a Lewis basic site roughly 0.3 nm to be sweet, it needs to possess a hydrogen bond donor, and a Lewis basic site roughly 0.3 nm apart  apart [31,32]. For enhanced sweetness compared to sucrose, the importance of a third, hydrophobic, [31,32]. For enhanced sweetness compared to sucrose, the importance of a third, hydrophobic, site  site was established [33]. In sucralose, two chlorine atoms present in the fructose portion of the was established [33]. In sucralose, two chlorine atoms present in the fructose portion of the molecule  molecule comprise the hydrophobic site. comprise the hydrophobic site.    Generally, highly intense sweeteners tend to be more hydrophobic, which is suggested to give Generally, highly intense sweeteners tend to be more hydrophobic, which is suggested to give  rise to stronger absorption to taste bud tissue in contrast to simpleto sugars, which are more hydrophilic, rise  to  stronger  absorption  to  taste  bud  tissue  in  contrast  simple  sugars,  which  are  more  less sweet and weakly absorbed to the taste buds. This trend can be clearly observed in the series of hydrophilic, less sweet and weakly absorbed to the taste buds. This trend can be clearly observed in  synthetic halogenated analogs of sucrose (Figure 8) [29]. the series of synthetic halogenated analogs of sucrose (Figure 8) [29]. 

  Figure  8. 8.  The  relative  sweetness sweetness  of of some some disaccharides disaccharides and and halogenated halogenated derivatives. derivatives.  Increased Increased  Figure The relative hydrophobicity increases perceived sweetness.  hydrophobicity increases perceived sweetness.

3. Alkyl Halide Natural Products  3. Alkyl Halide Natural Products Natural products have always inspired the development of novel medicines, as exhibited by the  Natural products have always inspired the development of novel medicines, as exhibited by fact that between 1981 and 2014 approximately 40% of all new approved drugs were based on natural  the fact that between 1981 and 2014 approximately 40% of all new approved drugs were based on products  [34].  It [34]. is  therefore  instructive  to  describe  the the biological  activity  natural products It is therefore instructive to describe biological activityof  ofsome  some halogenated  halogenated secondary metabolites that may serve as drug candidates. It is an interesting historical note that for a  secondary metabolites that may serve as drug candidates. It is an interesting historical note that for a long  time  the  chemistry  community  believed  very  few  halogenated  natural  products  existed.  However, recent years have witnessed a surge in the isolation of halogenated molecules from marine 

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organisms,  counting  more  than  5000  today  [35].  This,  in  time,  could  thus  translate  into  a  greater  Mar. Drugs 2016, 14, 206 number of alkyl chloride and bromide containing drug candidates. 

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3.1. Halomon 

Mar. Drugs 2016, 14, 206  long time the chemistry community believed very few halogenated natural products existed.

7 of 11  However, recentHalomon (Figure 9) was isolated in 1975 from the red algae Portieria hornemannii [36]. Seventeen  years have witnessed a surge in the isolation of halogenated molecules from marine organisms, years later it produced one of the most extreme cases of differential cytotoxicity in a National Cancer  organisms,  counting  more  than  5000  today  [35].  could This,  in  time,  could into thus  translate  into  a of greater  counting more than 5000 today [35]. This, in time, thus translate a greater number alkyl Institute NCI‐60 human tumor cell line screen [37]. The compound was selected for preclinical drug  number of alkyl chloride and bromide containing drug candidates.  chloride and bromide containing drug candidates. development,  but  then  later  was  dropped  due  to  lack  of  material  [38].  Even  though  the  detailed  3.1. Halomon  3.1. Halomon mechanism of action is unknown, it has been suggested that the activity is due to the inhibition of  DNA  methyltransferase,  an  important  target  for  combatting  cancer  because  of  its  tendency  to  Halomon (Figure 9) was isolated in 1975 from the red algae Portieria hornemannii [36]. Seventeen  Halomon (Figure 9) was isolated in 1975 from the red algae Portieria hornemannii [36]. Seventeen hypermethylate tumor suppressing regions in tumor suppressing cells [39]. Computational analysis  years later it produced one of the most extreme cases of differential cytotoxicity in a National Cancer  years later it produced one of the most extreme cases of differential cytotoxicity in a National Cancer of the cytotoxicity profile of halomon has suggested that the activity cannot be attributable to simple  Institute NCI‐60 human tumor cell line screen [37]. The compound was selected for preclinical drug  Institute NCI-60 human tumor cell line screen [37]. The compound was selected for preclinical drug nonspecific alkylation reactions in the body [40]. Investigations into the mechanism of action of this  development,  dropped  due due  to to  lack lack of of material material [38]. [38].  Even  the  detailed detailed  development, but  but then  then later  later was  was dropped Even though  though the molecule are ongoing within our laboratory through collaborations [41]. Initial results suggest that  mechanism of action is unknown, it has been suggested that the activity is due to the inhibition of  mechanism of action is unknown, it has been suggested that the activity is due to the inhibition the unnatural enantiomer, (−)‐halomon, is inactive against a series of cancers that are sensitive to (+)‐ DNA  methyltransferase,  an an important  target  of DNA methyltransferase, important targetfor  forcombatting  combattingcancer  cancerbecause  becauseof  of its  its tendency  tendency to  to halomon [42].  hypermethylate tumor suppressing regions in tumor suppressing cells [39]. Computational analysis  hypermethylate tumor suppressing regions in tumor suppressing cells [39]. Computational analysis of the cytotoxicity profile of halomon has suggested that the activity cannot be attributable to simple  of the cytotoxicity profile of halomon has suggested that the activity cannot be attributable to simple nonspecific alkylation reactions in the body [40]. Investigations into the mechanism of action of this  nonspecific alkylation reactions in the body [40]. Investigations into the mechanism of action of this molecule are ongoing within our laboratory through collaborations [41]. Initial results suggest that  molecule are ongoing within our laboratory through collaborations [41]. Initial results suggest that the unnatural enantiomer, (−)‐halomon, is inactive against a series of cancers that are sensitive to (+)‐ the unnatural enantiomer, (−)-halomon, is inactive against a series of cancers that are sensitive to halomon [42].  (+)-halomon [42].

  Figure 9. The structure of (+)‐halomon, a pentahalogenated myrcene derivative. 

3.2. Lapachone  β‐lapachone  is  a  natural  product  present  in  the  bark  of  the  lapacho  tree,  which  grows    large  spectrum  of  pharmacological  predominantly  in  Brazil  (Figure  10).  It  is  endowed  with  a  activities, including antibacterial [43], antifungal [43], and antimalarial [44,45] activities. It is also a  Figure 9. The structure of (+)‐halomon, a pentahalogenated myrcene derivative.  Figure 9. The structure of (+)-halomon, a pentahalogenated myrcene derivative. potential treatment for prostate and non‐small cell lung cancers that has been evaluated in clinical  3.2. Lapachone  trials [46].  3.2. Lapachone When testing analogs of β‐lapachone, researchers discovered that bromination at the C3 position  β‐lapachone  is  in  of  the the  lapacho lapacho  tree, tree,  which which  grows grows  β-lapachone is a  a natural  natural product  product 50present  present in the  the bark  bark of enhances antiplasmoidal activity [45] (IC  2.7 μM vs. 4.1 μM against Plasmodium falciparum, strain  predominantly inin Brazil Brazil  (Figure  is  endowed  large  spectrum  of  pharmacological  predominantly (Figure 10).10).  It isIt  endowed with awith  largea spectrum of pharmacological activities, F 32) and cytotoxicity [47] (IC 50 0.13 μM vs. 0.27 μM against promyelocytic leukemia HL‐60 cell lines,  activities, including antibacterial [43], antifungal [43], and antimalarial [44,45] activities. It is also a  including antibacterial [43], antifungal [43], and antimalarial [44,45] activities. It is also a potential MTT  assay).  To  date,  no  study  has  reported  testing  of  individual  enantiomers,  nor  chlorinated  potential treatment for prostate and non‐small cell lung cancers that has been evaluated in clinical  treatment for prostate and non-small cell lung cancers that has been evaluated in clinical trials [46]. derivatives.  trials [46].  When testing analogs of β‐lapachone, researchers discovered that bromination at the C3 position  Me Me Me Me enhances antiplasmoidal activity [45] (IC50 2.7 μM vs. 4.1 μM against Plasmodium falciparum, strain  Br O O F 32) and cytotoxicity [47] (IC50 0.13 μM vs. 0.27 μM against promyelocytic leukemia HL‐60 cell lines,  MTT  assay).  To  date,  no  study  has  reported  testing  of  individual  enantiomers,  nor  chlorinated  derivatives.  O O O Me Me -lapachone O

O Me Me (±)-3-bromo--lapachone   Br O

Figure 10. The structures of β‐lapachone and its more active analog, 3‐bromo‐β‐lapachone.  Figure 10. The structures of β-lapachone and its more active analog, 3-bromo-β-lapachone.

3.3. Astins  O researchers discovered O that bromination at the C3 position When testing analogs of β-lapachone, O O Astins A–I are a family of cyclic pentapeptides isolated from the medicinal plant Aster tataricus  enhances antiplasmoidal activity [45] (IC50 2.7 µM vs. 4.1 µM against Plasmodium falciparum, strain F 32) -lapachone (±)-3-bromo--lapachone   (Figure  11).  They  contain a  16‐membered  ring against of  several  non‐coded leukemia amino acids, including a  β,γ‐ and cytotoxicity [47] (IC50 0.13 µM vs. 0.27 µM promyelocytic HL-60 cell lines, MTT dichlorinated proline residue [48]. Their antitumor activity was assayed using Sarcoma 180 ascites in  assay). ToFigure 10. The structures of β‐lapachone and its more active analog, 3‐bromo‐β‐lapachone.  date, no study has reported testing of individual enantiomers, nor chlorinated derivatives. mice. The effectiveness was evaluated in terms of the tumor growth ratio. At 5 mg/kg/day astins A,  3.3. Astins  Astins A–I are a family of cyclic pentapeptides isolated from the medicinal plant Aster tataricus  (Figure  11).  They  contain a  16‐membered  ring  of  several  non‐coded  amino acids, including a  β,γ‐ dichlorinated proline residue [48]. Their antitumor activity was assayed using Sarcoma 180 ascites in  mice. The effectiveness was evaluated in terms of the tumor growth ratio. At 5 mg/kg/day astins A, 

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3.3. Astins Astins A–I are a family of cyclic pentapeptides isolated from the medicinal plant Aster tataricus (Figure 11). They contain a 16-membered ring of several non-coded amino acids, including a β,γ-dichlorinated proline residue [48]. Their antitumor activity was assayed using Sarcoma 180 ascites Mar. Drugs 2016, 14, 206  8 of 11  in mice. The effectiveness was evaluated in terms of the tumor growth ratio. At 5 mg/kg/day astins A, B and C gave the GR (tumor growth ratio) values of 40%, 26% and 45%, respectively, whereas Mar. Drugs 2016, 14, 206  8 of 11  the B and C gave the GR (tumor growth ratio) values of 40%, 26% and 45%, respectively, whereas the  otherother natural astins (F, G, I) and the derivatives of dechlorinated proline residues did not inhibit the  natural astins (F, G, I) and the derivatives of dechlorinated proline residues did not inhibit the B and C gave the GR (tumor growth ratio) values of 40%, 26% and 45%, respectively, whereas the  tumor growth at 10 mg/kg/day. The presence of cis dechlorinated proline residues was concluded to tumor growth at 10 mg/kg/day. The presence of cis dechlorinated proline residues was concluded to  be another natural astins (F, G, I) and the derivatives of dechlorinated proline residues did not inhibit the  important structural motif for astins for antitumor activity. be an important structural motif for astins for antitumor activity.  tumor growth at 10 mg/kg/day. The presence of cis dechlorinated proline residues was concluded to  be an important structural motif for astins for antitumor activity. 

  Figure 11. The general structure of compounds belonging to the family of astins.  Figure 11. The general structure of compounds belonging to the family  of astins. Figure 11. The general structure of compounds belonging to the family of astins. 

3.4. Forazoline 

3.4. Forazoline

Forazoline  A  was  recently  isolated  from  the  marine  Actinomadura  sp.  (Figure  12)  [49].  It  3.4. Forazoline 

Forazoline A was recently isolated from the marine Actinomadura sp. (Figure 12) [49]. It demonstrated demonstrated in vivo antifungal efficacy, comparable to amphotheracin B, against C. albicans. It was  Forazoline  A  was  recently  isolated  from  the  marine  Actinomadura  sp.  (Figure  12)  [49].  It  in vivo antifungal comparable amphotheracin B, against C. albicans. It was also found also  found  to efficacy, be  nontoxic  in  mice. toFurther  experiments  suggested  that  forazoline  affects  cell to be demonstrated in vivo antifungal efficacy, comparable to amphotheracin B, against C. albicans. It was  membranes, potentially through the disregulation of phospholipid homeostasis. It is unknown at this  nontoxic in mice. Further experiments suggested that forazoline affects cell membranes, potentially also  found  to  be  nontoxic  in  mice.  Further  experiments  suggested  that  forazoline  affects  cell  stage how much of the biological activity is attributable to the presence of the alkyl chloride moiety.  through the disregulation of phospholipid homeostasis. It is unknown at this stage how much of the membranes, potentially through the disregulation of phospholipid homeostasis. It is unknown at this  biological activity is attributable to the presence of the alkyl chloride moiety. stage how much of the biological activity is attributable to the presence of the alkyl chloride moiety. 

  Figure 12. Structure of the recently isolated forazoline A.    Figure 12. Structure of the recently isolated forazoline A. 

4. Summary and Outlook  Figure 12. Structure of the recently isolated forazoline A. This  review  has  aimed  to  illustrate  the  medical  benefit  of  chiral  alkyl  halides,  as  well  as  the  4. Summary and Outlook 

4. Summary and Outlook features of these compounds that play a key role in their activity. Alkyl halides, especially chlorides,  This  review  has  aimed  to  illustrate  the  medical  benefit  of  chiral  alkyl  halides,  as  well  as  the  are often stable, which is underscored by the number of compounds in the clinic and food industry 

features of these compounds that play a key role in their activity. Alkyl halides, especially chlorides,  This review has aimed to illustrate the medical benefit of chiral alkyl halides, as well as the containing these motifs. Halogenation, and the stereochemistry of the halogen‐bearing carbons can  are often stable, which is underscored by the number of compounds in the clinic and food industry  features of these compounds that play a key role in their activity. Alkyl halides, especially chlorides, significantly alter bioactivity. This can happen through increased lipophilicity, which leads to better  containing these motifs. Halogenation, and the stereochemistry of the halogen‐bearing carbons can  are often stable, which is underscored byhalogen  the number compounds in the clinic and food industry pharmacokinetic  properties.  However,  atoms ofcan  also  play  key  roles  in  binding  through  significantly alter bioactivity. This can happen through increased lipophilicity, which leads to better  containing these motifs. Halogenation, the stereochemistry of the halogen-bearing carbons halogen  bonding  interactions,  and,  in and a  number  of  cases,  the  exact  roles  of  halogens  are  not  fully  can pharmacokinetic  properties.  However,  halogen  atoms  can  also  play  key  roles  in  binding  through  significantly alter bioactivity. This number  can happen through increasednatural  lipophilicity, which leadswith  to better elucidated.  Finally,  a  growing  of  isolated  halogenated  products  endowed  halogen  bonding  interactions,  and,  in  a  number  of  cases,  the  exact  roles  of  halogens  are  not  fully  unique  bioactivity  show  promise  for  further  Looking  it  is  that through the  pharmacokinetic properties. However, halogendevelopment.  atoms can also playforward,  key roles in clear  binding elucidated.  Finally,  a  growing  number  of  isolated  halogenated  natural  products  endowed  with  synthetic community has a huge opportunity for the understanding and prediction of the properties  halogen bonding interactions, and, in number of cases, the exact forward,  roles of halogens unique  bioactivity  show  promise  for afurther  development.  Looking  it  is  clear  are that not the fully of  chiral alkyl  halides  through  molecular  design.  Looking  forward, it  is  also  clear  that in  order  to  synthetic community has a huge opportunity for the understanding and prediction of the properties  better understand and predict the properties of chiral alkyl halides, the synthetic community needs  of  chiral alkyl  halides  through  molecular  design.  Looking  forward, it  is  also  clear  that in  order  to  novel, highly selective methods for their installation.  better understand and predict the properties of chiral alkyl halides, the synthetic community needs  novel, highly selective methods for their installation. 

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elucidated. Finally, a growing number of isolated halogenated natural products endowed with unique bioactivity show promise for further development. Looking forward, it is clear that the synthetic community has a huge opportunity for the understanding and prediction of the properties of chiral alkyl halides through molecular design. Looking forward, it is also clear that in order to better understand and predict the properties of chiral alkyl halides, the synthetic community needs novel, highly selective methods for their installation. Acknowledgments: This work was supported by Stanford University and the National Institutes of Health (R01 GM114061). Conflicts of Interest: The authors declare no conflict of interest.

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