Synthesis and Cytotoxicity Evaluation of Spirocyclic Bromotyrosine Clavatadine C Analogs

Patel, Piyush A.; Bruun, Tanja; Ilina, Polina; Mäkkylä, Heidi; Lempinen, Antti; Yli‐Kauhaluoma, Jari; Tammela, Päivi; Kiuru, Paula

doi:10.3390/md19070400

Cited by 7 publications

(17 citation statements)

References 20 publications

(63 reference statements)

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“…Oximination and dibromospirocyclization of L-tyrosine tert-butyl ester ultimately led to both clavatadine C (3) and D (4) in a five-step, convergent synthesis from commercially available materials and in overall yields of 30-37% and 26-39%, respectively. In contrast to a prior report that found clavatadine C (3) to be moderately active against four cancer cell lines 10 but in agreement with recent work by Kiuru and co-workers, 8 our sample displayed little to no cytotoxicity. On the other hand, clavatadine D (4) moderately inhibited growth in a wide range of cancer cell types.…”

Section: Discussionsupporting

confidence: 92%

“…[5][6][7] Clavatadine A (1), B (2), and C (3) were recently prepared by total synthesis using a convergent, early stage guanidinylation approach. [8][9][10][11] Due to substantial metabolite crossover that exists amongst members of this order, the quest to discover new compounds amid a hearty mix of biosynthetically related secondary metabolites often reacquaints researchers with previously discovered chemical entities. For example, the isolation effort that unearthed clavatadines C (3), D (4), and E (5) from Suberea clavata also led to the recovery of structurally related spirocyclic natural products purealidin L (6), aplysinamisine II (7), and aerophobin 1 (8) (Chart 2).…”

Section: Introductionmentioning

confidence: 99%

“…Oceanapia sp. compound 14 (R = CH 2 CH 2 CH 2 NH 2 ; X = H) purealidin O (15, R = CH 3 ; X = OH) (16, R = H; X = Br) purpuramine L (17, R = CH 2 CH 2 CH 2 NH 2 ; X = H) aplysamine 4 (18, R = CH 2 CH 2 CH 2 NH 2 ; X = Br) Examples of naturally occurring spiroisoxazolines(6)(7)(8)(9)(10)(11)(12) that resemble clavatadine C (3) and D (4) and marine sponge-derived brominated phenols(13)(14)(15)(16)(17)(18)(19) reminiscent of clavatadine E (5). purealidin L (6, n = 1) aplysinamisine II (7, n = 2)…”

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confidence: 99%

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Total Synthesis and Biological Evaluation of Clavatadines C-E

Chamberland

Maxfield

Payne

2022

Preprint

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Described herein is the application of a convergent and protecting-group avoidant approach that led to the first total synthesis of the marine natural products clavatadine D (4) and E (5), and the second total synthesis of clavatadine C (3). In each case, a key amide-coupling afforded an immediate precursor of each natural product in rapid fashion from structurally similar western and eastern portions that derived from an ester of L-tyrosine and butane-1,4-diamine, respectively. A deprotection step free of detectable by-products cleanly provided the remaining known members of the clavatadine family of natural products. Each total synthesis required five steps (longest linear sequence) with overall yields of 30-37%, 26-39%, and 28-50% for clavatadine C (3), D (4), and E (5), respectively. A screen of their potential anticancer activity against the NCI-60 cell line panel revealed cytotoxicity levels up to 38% across a broad spectrum of tumor types. Although clavatadine C (3) was relatively benign, clavatadine D (4) exhibited 20-38% growth inhibition against a wide array of cancer cell types including leukemia, non-small cell lung, colon, ovarian, and breast. Clavatadine E (5) was active against two types of human brain tumors.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Total Synthesis and Biological Evaluation of Clavatadines C-E

Chamberland

Maxfield

Payne

2022

Preprint

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“… 5 − 7 Clavatadine A ( 1 ), B ( 2 ), and C ( 3 ) were recently prepared by total synthesis using a convergent, early-stage guanidinylation approach. 8 − 11 …”

Section: Introductionmentioning

confidence: 99%

“…An additional focus was to develop a convergent approach that would be amenable to the preparation of analogues for biological evaluation. For example, because cytotoxicity relies most heavily upon the structure of the tail portion in clavatadine C analogues, 8 it was desired to construct the central amide bond as late as possible during each synthesis to maximize overall yield according to the principle of convergence. Thus, the principal goal in each synthesis was to incorporate the tail portion in the penultimate step.…”

Section: Introductionmentioning

confidence: 99%

Total Synthesis and Biological Evaluation of Clavatadines C–E

2022

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We described herein the application of a convergent and protecting-group avoidant approach that led to the first total synthesis of the marine natural products clavatadine D ( 4 ) and E ( 5 ), and the second total synthesis of clavatadine C ( 3 ). In each case, a key amide-coupling afforded an immediate precursor of each natural product in a rapid manner from structurally similar western and eastern portions that derived from an ester of l -tyrosine and butane-1,4-diamine, respectively. A deprotection step free of detectable byproducts cleanly provided the remaining known members of the clavatadine family of natural products. Each total synthesis required five steps (longest linear sequence) with overall yields of 30–37%, 26–39%, and 28–50% for clavatadine C ( 3 ), D ( 4 ), and E ( 5 ), respectively. A screen of their potential anticancer activity against the NCI-60 cell line panel revealed cytotoxicity levels up to 38% across a broad spectrum of tumor types. Although clavatadine C ( 3 ) was relatively benign, clavatadine D ( 4 ) exhibited 20–38% growth inhibition against a wide array of cancer cell types including leukemia, non-small-cell lung, colon, ovarian, and breast. Clavatadine E ( 5 ) was active against two types of human brain tumors.

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On the Halogenation of Tyrosine N‐Oxime Methyl Ester

Payne,

Fossatti,

Chamberland

2024

Eur J Org Chem

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Efficient syntheses of mono‐, di‐, and heterodihalogenated derivatives of tyrosine N‐oxime methyl ester are reported. Monohalogenation with N‐bromosuccinimide (NBS), N‐chlorosuccinimide (NCS) or N‐iodosuccinimide (NIS) was optimized by addition of acid to suppress dihalogenation, affording bromo, chloro, and iodo derivatives in 71%, 50‐53%, and 78‐80% yields, respectively. Homodihalogenation utilized a two‐step, one‐flask process via a spirocyclic intermediate, yielding dibromo, dichloro, and diiodo analogues, respectively (75‐76%, 54‐56%, 79‐80%). This strategy was extended to synthesize heterodihalogenated bromochloro, bromoiodo, and chloroiodo derivatives from monohalogenated analogues (50‐77%). Key to this approach was the formation of an oxidized spirocyclic intermediate using excess N‐halosuccinimide, followed by Na₂S₂O₄ reduction. This method ensures complete conversion and simplifies purification. Nine halogenated building blocks were prepared. These methods provide practical access to versatile precursors for natural product synthesis and derivatization, offering potential for diverse synthetic applications including regioselective palladium‐catalyzed couplings.

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Synthesis and Cytotoxicity Evaluation of Spirocyclic Bromotyrosine Clavatadine C Analogs

Cited by 7 publications

References 20 publications

Total Synthesis and Biological Evaluation of Clavatadines C-E

Total Synthesis and Biological Evaluation of Clavatadines C-E

Total Synthesis and Biological Evaluation of Clavatadines C–E

On the Halogenation of Tyrosine N‐Oxime Methyl Ester

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