Synthesis and biological evaluation of unnatural derivatives of narciclasine: 7-aza-nornarciclasine and its N-oxide

Abstract

Several unnatural derivatives of narciclasine were prepared in which the C-7 carbon was replaced with nitrogen. The 7-aza derivative and its N-oxide were prepared by the coupling of iodopicolinic acid with a conduramine unit derived chemoenzymatically from bromobenzene. Intramolecular Heck reaction was used to construct the carbostyryl ring system. The compounds were submitted to biological screening against cancer cell lines. Full experimental and spectra data are provided for all new compounds.

Synthesis of Amaryllidaceae Constituents and Unnatural Derivatives

“…[163] Thestrategy employed in the synthesis of 10-aza-narciclasine (424)was similar to that which was used in the production of 7-aza-nornarciclasine analogues and involved the coupling of the aromatic A-ring fragment 422 with conduramine 415, followed by aH eck reaction to construct the B-ring (Scheme 86). [162,163] Thes ynthesis of the aromatic A-ring fragment 422 however,f ollowed as ignificantly different pathway than that previously utilized. This process involved the production of 2,3-methylenedioxy-5-bromopyridine (420) from furfural (397)i nafive step sequence by ak nown procedure [184] (Scheme 86).…”

“…Having previously worked on triazole synthesis through Huisgen cycloaddition [180] chemistry, [181] Gonzalez designed the unnatural pancratistatin/7-deoxypancratistatin analogues 395 and 396 based upon the idea that the aromatic triazole functionality could act as asurrogate for the aromatic A-ring, with the ester moiety of analogue 395 acting as amimic for the C-7 hydroxy functionality of pancratistatin (possibly by hydrolysis to the corresponding acid). [160] Although the triazole functionality is aromatic,t he differences between the A-ring of analogues 395 and 396 and the A-ring of the natural compounds are significant and it is difficult to see how the functionality of these designed analogues would effectively mimic those of the natural compounds.S imilar to the syntheses by Hudlicky [11,42,45,47,49,52,60,71,81,144,147,149,151,159,162,163] and Banwell, [31a, 70, 74, 89] the approach to analogues 395 and 396 utilized the enzymatic metabolite of bromobenzene,d iol 74,a st he starting material. [57] Tw o routes were envisioned for the production of analogues 395 and 396,i nb oth of which azide 387 was used as ac ommon intermediate.D iol 74 was protected as its corresponding acetonide before being subjected to epoxidation and the opening of the epoxide with sodium azide (Scheme 79).…”

“…[41,59,147,149,151,162] None report modifications of the ring itself.H aving established the importance of the C-7 hydroxy functionality for anti-cancer activity, [52,159] 7-azanornarciclasine analogues 418 and 419 were designed, based upon the hypothesis that the N-oxide moiety in compound 419 could mimic the donor-acceptor functionality of the 7hydroxy phenanthridone moiety of natural narciclasine (3). [162] Thes trategy that was utilized in the synthesis of these analogues was based upon the coupling of conduramine 415 with the aromatic fragment 413,f ollowed by aH eck coupling to establish the B-ring, in amanner similar to the one applied in the synthesis of lycoricidine (4). [81] Thearomatic coupling partner 413 was synthesized by the directed ortho-metalation of picolinic acid (412)(Scheme 84).…”

“…With the amide 423 in hand, the synthesis of 10-azanarciclasine (424)p roceeded in as imilar manner to the previously discussed preparation of 7-aza-nornarciclasine (418). [162] This process involved Boc-protection of the amide nitrogen, followed by Heck coupling and full deprotection to afford the desired compound, 10-aza-narciclasine (424) (Scheme 87).…”

Carbon Nanotube–Ruthenium Hybrids for the Partial Reduction of 2‐Nitrochalcones: Easy Access to Quinoline N‐Oxides

“…Quinolines and quinoline N ‐oxides make up parts of many naturally occurring compounds and are of biological significance . In particular, quinoline N ‐oxides exhibit antitumor and antimalarial activities . In addition, the quinoline N ‐oxide core has been found in drugs that activate microsomal Na/K‐ATPase .…”