Full details of the development of a direct coupling of catharanthine with vindoline to provide vinblastine are described along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)-NaBH 4 /air solution leads to oxidation of the C15′-C20′ double bond and reduction of the intermediate iminium ion directly providing vinblastine (40-43%) and leurosidine (20-23%), its naturally occurring C20′ alcohol isomer. The yield of coupled products, which exclusively possess the natural C16′ stereochemistry, approaches or exceeds 80% and the combined yield of the isomeric C20′ alcohols is >60%. Preliminary studies of Fe(III)-NaBH 4 /air oxidation reaction illustrate a generalizable trisubstituted olefin scope, identified alternatives to O 2 trap at the oxidized carbon, provides a unique entry into C20′ functionalized vinblastines, and affords initial insights into the observed C20′ diastereoselectivity. The first disclosure of the use of exo-catharanthine proceeding through Δ 19′,20′ -anhydrovinblastine in such coupling reactions is also detailed with identical stereochemical consequences. Incorporating either a catharanthine N-methyl group or a vindoline N-formyl group precludes Fe(III)-promoted coupling, whereas the removal of the potentially key C16 methoxy group of vindoline does not adversely impact the coupling efficiency. Extension of these studies provided a total synthesis of vincristine (2) via N-desmethylvinblastine (36, also a natural product), 16-desmethoxyvinblastine (44) and 4-desacetoxy-16-desmethoxyvinblastine (47) both of which we can now suggest are likely natural products produced by C. roseus, desacetylvinblastine (62) and 4-desacetoxyvinblastine (59), as well as a series of key analogues bearing systematic modifications in the vindoline subunit. Their biological evaluation provided additional insights into the key functionality within the vindoline subunit contributing to the activity and sets the foundation on which further, more deep-seated changes in the structures of 1 and 2 will be explored in future studies.
A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12)(13)(14) revealed that the optimal position for substitution was the meta-position with selected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect of substitution on the pyridine ring of 2f was also examined. A series of small, non-aromatic C5-substituents was also explored and revealed that the K i follows a well-defined correlation with the Hammett σ p constant (ρ = 3.01, R 2 = 0.91) in which electron-withdrawing substituents enhance potency leading to inhibitors with K i 's as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases reversing the 100-fold preference of 20a (C5 substituent = H) for the enzyme TGH.Fatty acid amides are an important new class of lipid signaling molecules that modulate a number of physiological processes. Two endogenous fatty acid amides, anandamide (1a) 1 and oleamide (1b), 2-4 have emerged as prototypical members of this class that serve as chemical messengers (Figure 1). Anandamide (1a), which was only discovered a little more than a decade ago and is the most recognizable member of the endogenous fatty acid ethanolamides, 5 binds and activates both the central type-1 (CB1) and peripheral type-2 (CB2) cannabinoid receptors. Anandamide (1a), and members of the cannabinoid family, 6 have been implicated in the modulation of nociception, 7-9 feeding, 10,11 emesis, anxiety, 12 cell proliferation, 13,14 inflammation, 15 memory 16 and neuroprotection after brain injury. 17 Thus, the cannabinoids have clinical relevance for analgesia, anxiety, epilepsy, cachexia, cancer, and Alzheimer's disease as well as other neurodegenerative diseases. 18-20 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOleamide (1b) was found to accumulate in the cerebrospinal fluid of animals under conditions of sleep deprivation and to induce physiological sleep in a dose dependent manner where it reduced motility, shortened the sleep induction period, and lengthened the time spent in slow wave sleep 2 at the expense of wakening. 2,4 In a structurally specific manner, it was found to modulate serotonergic systems 21-23 and GABAergic transmission, 24,25 block glial gap junction cell-cell communication, 26,27 decrease body temperature and locomotor activity, 28 and exhibit the characteristic in vivo analgesic and cannabinoid behavorial effects of anandamide, 21,29 albeit without direct cannabinoid receptor activation. It has been suggested that the cannabinoid behavorial effects of oleamide (1b) may be mediated through an as yet unknown distinct pharmacological target. 24 Because oleamide (1b) may play a critical role in sleep, it may provide an exciting therapeutic potential for the development of sle...
A systematic study of the structure-activity relationships (SAR) of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, K i = 2.6 nM) with 5hh (aryl = 3-Cl-Ph, K i = 900 pM) being 5-fold more potent than 2b. Conformationally-restricted C2 side chains were examined and many provided exceptionally potent inhibitors of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO 2 ), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, K i = 3 nM or 13d, 2-position OH, K i = 8 nM) comparable in potency to 2b. Proteomicwide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases.The enzyme fatty acid amide hydrolase (FAAH) is the primary catabolic regulator of several bioactive lipid amides in vivo, including anandamide (1a) and oleamide (1b). 1-4 The central nervous system distribution of FAAH suggests that it degrades neuromodulating fatty acid amides at their sites of action and is intimately involved in their regulation. 5 Fatty acid amide hydrolase is currently the only characterized mammalian enzyme that is in the amidase signature family bearing an unusual catalytic Ser-Ser-Lys triad. 1,4,6-8 Recently, the crystal structure of FAAH cocrystallized with an irreversibly-bound arachidonyl fluorophosphonate confirmed its unusual catalytic triad and provided structural details of this enzyme. 1 Both anandamide (1a) 9 and oleamide (1b) 10-12 have emerged as prototypical members of the class of bioactive lipid amides 13,14 that serve as chemical messengers (Figure 1). Anandamide (1a), the most recognized member of the endogenous fatty acid ethanolamides, 15 binds and activates both the central type-1 (CB1) and peripheral type-2 (CB2) cannabinoid receptors. Anandamide (1a), and members of the cannabinoid family, 16 have been implicated in the modulation of nociception, 17-19 feeding, 20,21 emesis, anxiety, 22 cell proliferation, 23,24 inflammation, 25 memory 26 and neuroprotection after brain injury. 27 Thus, the Due to the potentially exciting therapeutic potential of inhibiting FAAH, there has been increasing interest in the development of potent inhibitors (Figure 2). 22,45-60 These include the discovery that the endogenous sleep-inducing molecule 2-octyl α-bromoacetoacetate is an effective FAAH inhibitor, 55 a series of reversible inhibitors bearing an electrophilic ketone 46,54,56 (e.g., trifluoromethyl ketone-based) that have not proven selective for FAAH over other mammalian serine hydrolases 61 and a set of irreversible inhibitor...
The synthesis and evaluation of a refined series of α-ketoheterocycles based on the oxazole 2 (OL-135) incorporating systematic changes in the central heterocycle bearing a key set of added substituents are described. The nature of the central heterocycle, even within the systematic and minor perturbations explored herein, significantly influenced the inhibitor activity: 1,3,4-oxadiazoles and 1,2,4-oxadiazoles 9 > tetrazoles, the isomeric 1,2,4-oxadiazoles 10, 1,3,4-thiadiazoles > oxazoles including 2 > 1,2-diazines > thiazoles > 1,3,4-triazoles. Most evident in these trends is the observation that introduction of an additional heteroatom at position 4 (oxazole numbering, N > O > CH) substantially increases activity that may be attributed to a reduced destabilizing steric interaction at the FAAH active site. Added heterocycle substituents displaying well defined trends may be utilized to enhance the inhibitor potency and, more significantly, to enhance the inhibitor selectivity. These trends, exemplified herein, emerge from both enhancements in the FAAH activity and simultaneous disruption of binding affinity for competitive off-target enzymes.
A series of alpha-ketooxazoles containing conformational constraints in the flexible C2 acyl side chain of 2 (OL-135) and representative oxazole C5 substituents were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH). Exceptionally potent and selective FAAH inhibitors emerged from the series (e.g., 6, Ki = 200 and 260 pM for rat and rhFAAH). With simple and small C5 oxazole substituents, each series bearing a biphenylethyl, phenoxyphenethyl, or (phenoxymethyl)phenethyl C2 side chain was found to follow a well-defined linear relationship between -log Ki and Hammett sigmap of a magnitude (rho = 2.7-3.0) that indicates that the substituent electronic effect dominates, confirming its fundamental importance to the series and further establishing its predictive value. Just as significantly, the nature of the C5 oxazole substituent substantially impacts the selectivity of the inhibitors whereas the effect of the C2 acyl chain was more subtle but still significant even in the small series examined. Combination of these independent features, which display generalized trends across a range of inhibitor series, simultaneously improves FAAH potency and selectivity and can provide exquisitely selective and potent FAAH inhibitors.
N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole 2 are reported as prototypical members of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumor agents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carry an intrinsic higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives (tunable N-O bond cleavage) increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (<0.1-0.01% free drug release), pH 7.0 phosphate buffer, and exhibit a robust half-life in human plasma (t ½ = 3 h). Characterization of a representative O-(acylamino) prodrug in vivo indicate that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole 2 ) indicating that not only is the free drug effectively released from the inactive prodrug, but that they offer additional advantages related to a controlled or targeted release in vivo.
The design, synthesis, and evaluation of a predictably more potent analogue of CC-1065 entailing the substitution replacement of a single skeleton atom in the alkylation subunit are disclosed and was conducted on the basis of design principles that emerged from a fundamental parabolic relationship between chemical reactivity and cytotoxic potency. Consistent with projections, the MeCTI (7-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one) alkylation subunit as well as its isomer iso-MeCTI (6-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[2,3-e]indol-4-one) were found to be 5-6 times more stable than the MeCPI alkylation subunit found in CC-1065 and slightly more stable than even the DSA alkylation subunit found in duocarmycin SA placing it at the point of optimally balanced stability and reactivity for this class of antitumor agents. Their incorporation into the key analogues of the natural products provided derivatives that surpassed the potency of MeCPI derivatives (3-10 fold) matching or slightly exceeding the potency of the corresponding DSA derivatives consistent with projections made based on the parabolic relationship. Notable of these, MeCTI-TMI proved to be as potent or slightly more potent than the natural product duocarmycin SA (DSA-TMI, IC 50 = 5 vs 8 pM) and MeCTI-PDE 2 proved to be 3-fold more potent than the natural product CC-1065 (MeCPI-PDE 2 , IC 50 = 7 vs 20 pM). Both exhibited efficiencies of DNA alkylation that correlate with this enhanced potency without impacting the intrinsic selectivity characteristic of this class of antitumor agents.
A systematic examination of the impact of the yatakemycin left and right subunits and their substituents is detailed along with a study of its unique three subunit arrangement (sandwiched vs extended and reversed analogues). The examination of the ca. 50 analogues prepared illustrate that within the yatakemycin three subunit structure, the subunit substituents are relatively unimportant and that it is the unique sandwiched arrangement that substantially increases the rate and optimizes the efficiency of its DNA alkylation reaction. This potentiates the cytotoxic activity of yatakemycin and its analogues overcoming limitations typically observed with more traditional compounds in the series (CC-1065, duocarmycins). Moreover, a study of the placement of the alkylation subunit within the three subunit arrangement (sandwiched vs extended and reversed analogues) indicates that it not only has a profound impact on the rate and efficiency of DNA alkylation but also controls and establishes the DNA alkylation selectivity as well, where both enantiomers of such sandwiched agents alkylate the same adenine sites exhibiting the same DNA alkylation selectivity independent of their absolute configuration.
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