Iron(III)/NaBH₄-Mediated Additions to Unactivated Alkenes: Synthesis of Novel 20′-Vinblastine Analogues

An Fe(III)/NaBH₄-mediated reaction for the functionalization of unactivated alkenes is described defining the alkene substrate scope, establishing the exclusive Markovnikov addition, exploring a range of free radical traps, examining the Fe(III) salt and initiating hydride source, introducing H₂O–cosolvent mixtures, and exploring catalytic variants. Its use led to the preparation of a novel, potent, and previously inaccessible C20′-vinblastine analogue

Potent Vinblastine C20′ Ureas Displaying Additionally Improved Activity Against a Vinblastine-Resistant Cancer Cell Line

A series of disubstituted C20′-urea derivatives of vinblastine were prepared from 20′-aminovinblastine that was made accessible through a unique Fe­(III)/NaBH₄-mediated alkene functionalization reaction of anhydrovinblastine. Three analogues were examined across a panel of 15 human tumor cell lines, displaying remarkably potent cell growth inhibition activity (avg. IC₅₀ = 200–300 pM), being 10–200-fold more potent than vinblastine (avg. IC₅₀ = 6.1 nM). Significantly, the analogues also display further improved activity against the vinblastine-resistant HCT116/VM46 cell line that bears the clinically relevant overexpression of Pgp, exhibiting IC₅₀ values on par with that of vinblastine against the sensitive HCT116 cell line, 100–200-fold greater than the activity of vinblastine against the resistant HCT116/VM46 cell line, and display a reduced 10–20-fold activity differential between the matched sensitive and resistant cell lines (vs 100-fold for vinblastine)

Iron(III)/NaBH₄-Mediated Additions to Unactivated Alkenes: Synthesis of Novel 20′-Vinblastine Analogues

An Fe(III)/NaBH₄-mediated reaction for the functionalization of unactivated alkenes is described defining the alkene substrate scope, establishing the exclusive Markovnikov addition, exploring a range of free radical traps, examining the Fe(III) salt and initiating hydride source, introducing H₂O–cosolvent mixtures, and exploring catalytic variants. Its use led to the preparation of a novel, potent, and previously inaccessible C20′-vinblastine analogue

Transannular Diels–Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Total Synthesis of a Unique Set of Vinblastine Analogues

A powerful tandem [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles initiated by a transannular [4 + 2] cycloaddition is detailed. An impressive four rings, four carbon–carbon bonds, and six stereocenters are set on each site of the newly formed central six-membered ring in a cascade thermal reaction that proceeds at temperatures as low as 80 °C. The resulting cycloadducts provide the basis for the synthesis of unique analogues of vinblastine containing metabolically benign deep-seated cyclic modifications at the C3/C4 centers of the vindoline-derived subunit of the natural product

A Remarkable Series of Vinblastine Analogues Displaying Enhanced Activity and an Unprecedented Tubulin Binding Steric Tolerance: C20′ Urea Derivatives

A systematic series of previously inaccessible key C20′ urea and thiourea derivatives of vinblastine were prepared from 20′-aminovinblastine that was made accessible through a unique Fe­(III)/NaBH₄-mediated alkene functionalization reaction of anhydrovinblastine. Their examination defined key structural features of the urea-based analogues that contribute to their properties and provided derivatives that match or exceed the potency of vinblastine by as much as 10-fold in cell-based functional assays, which is directly related to their relative tubulin binding affinity. In contrast to expectations based on apparent steric constraints of the tubulin binding site surrounding the vinblastine C20′ center depicted in an X-ray cocrystal structure, remarkably large C20′ urea derivatives are accommodated

Total Synthesis and Evaluation of Vinblastine Analogues Containing Systematic Deep-Seated Modifications in the Vindoline Subunit Ring System: Core Redesign

The total synthesis of a systematic series of vinblastine analogues that contain deep-seated structural modifications to the core ring system of the lower vindoline subunit is described. Complementary to the vindoline 6,5 DE ring system, compounds with 5,5, 6,6, and the reversed 5,6 membered DE ring systems were prepared. Both the natural <i>cis</i> and unnatural <i>trans</i> 6,6-membered ring systems proved accessible, with the latter representing a surprisingly effective class for analogue design. Following Fe­(III)-promoted coupling with catharanthine and in situ oxidation to provide the corresponding vinblastine analogues, their evaluation provided unanticipated insights into how the structure of the vindoline subunit contributes to activity. Two potent analogues (<b>81</b> and <b>44</b>) possessing two different unprecedented modifications to the vindoline subunit core architecture were discovered that matched the potency of the comparison natural products and both lack the 6,7-double bond whose removal in vinblastine leads to a 100-fold drop in activity

Efficacious Cyclic <i>N</i>‑Acyl <i>O</i>‑Amino Phenol Duocarmycin Prodrugs

Two novel cyclic <i>N</i>-acyl <i>O</i>-amino phenol prodrugs are reported as new members of a unique class of reductively cleaved prodrugs of the duocarmycin family of natural products. These prodrugs were explored with the expectation that they may be cleaved selectively within hypoxic tumor environments that have intrinsically higher concentrations of reducing nucleophiles and were designed to liberate the free drug without the release of an extraneous group. In vivo evaluation of the prodrug <b>6</b> showed that it exhibits extraordinary efficacy (<i>T</i>/<i>C</i> > 1500, L1210; 6/10 one year survivors), substantially exceeding that of the free drug, that its therapeutic window of activity is much larger, permitting a dosing ≥40-fold higher than the free drug, and yet that it displays a potency in vivo that approaches the free drug (within 3-fold). Clearly, the prodrug <b>6</b> benefits from either its controlled slow release of the free drug or its preferential intracellular reductive cleavage

A Novel, Unusually Efficacious Duocarmycin Carbamate Prodrug That Releases No Residual Byproduct

A unique heterocyclic carbamate prodrug of <i>seco</i>-CBI-indole₂ that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug. An in vivo evaluation of the prodrug found that its efficacy exceeded that of the parent drug, that its therapeutic window of efficacy versus toxicity is much larger than the parent drug, and that its slow free drug release permitted the safe and efficacious use of doses 150-fold higher than the parent compound

A Fundamental Relationship between Hydrophobic Properties and Biological Activity for the Duocarmycin Class of DNA-Alkylating Antitumor Drugs: Hydrophobic-Binding-Driven Bonding

Two systematic series of increasingly hydrophilic derivatives of duocarmycin SA that feature the incorporation of ethylene glycol units (<i>n</i> = 1–5) into the methoxy substituents of the trimethoxyindole subunit are described. These derivatives exhibit progressively increasing water solubility along with progressive decreases in cell growth inhibitory activity and DNA alkylation efficiency with the incremental ethylene glycol unit incorporations. Linear relationships of cLogP with −log IC₅₀ for cell growth inhibition and −log AE (AE = cell-free DNA alkylation efficiency) were observed, with the cLogP values spanning the productive range of 2.5–0.49 and the −log IC₅₀ values spanning the range of 11.2–6.4, representing IC₅₀ values that vary by a factor of 10⁵ (0.008 to 370 nM). The results quantify the fundamental role played by the hydrophobic character of the compound in the expression of the biological activity of members in this class (driving the intrinsically reversible DNA alkylation reaction) and define the stunning magnitude of its effect

Vinblastine 20′ Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance

A series of 180 vinblastine 20′ amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure–activity relationships and a structural model were developed in the studies which provided many such 20′ amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux