Synthesis and evaluation of hapalosin and analogs as MDR-reversing agents

O'Connell, Celeste E.; Salvato, Kathleen A.; Meng, Zhaoyang; Littlefield, Bruce A.; Schwartz, C. E.

doi:10.1016/s0960-894x(99)00243-7

Cited by 35 publications

(21 citation statements)

References 24 publications

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“…TBTU proved an efficient (33-64% yield) macrocyclization reagent using amide bonds as the key step. In earlier syntheses [149][150][151], the general trend has been to pre-form the depside links in linear precursors, then cyclizing at the tertiary amide bond. Reagents used include, DPPA/Pr i NEt 2 (23% yield), 2,4,6-trichlorobenzoyl chloride/DMAP/Pr i NEt 2 /toluene/room temp.…”

Section: Cyclodepsipeptidesmentioning

confidence: 99%

The cyclization of peptides and depsipeptides

Davies

2003

Journal of Peptide Science

416

241

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Constricting the peptide backbone into a more defined conformational form through cyclization is an activity evolved in nature and in synthetic work, the latter straddling only the most recent decades. The resulting conformational constraints increase the probability of an optimum response with bio-receptors. The purpose of this review is to highlight developments that have proved to be reasonably efficient in the macrocyclization of linear precursors into cyclic peptides and depsipeptides.

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Section: Cyclodepsipeptidesmentioning

confidence: 99%

The cyclization of peptides and depsipeptides

Davies

2003

Journal of Peptide Science

416

241

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“…The MCF-7 cells showed no change in sensitivities to VLB either in combination with hapalosin or alone, thereby attributing the changes in sensitivities to the ability of hapalosin to sensitize MCF-7/ADR cells to VLB due to the inhibition of P-gp transport function. Further efforts were made to synthesize hapalosin and its analogs with the aim of obtaining compounds with similar or superior MDR reversal activity [ 104 ]. Twenty-six structural analogs were synthesized with partial or less than desired MDR reversal activity, thus making hapalosin and its structural modifi cation open for research and the potential to develop agents with more potent MDR reversal abilities.…”

Section: Hapalosinmentioning

confidence: 99%

ABC Transporter Modulatory Drugs from Marine Sources: A New Approach to Overcome Drug Resistance in Cancer

Patel

Wang

Sim

et al. 2014

Resistance to Targeted Anti-Cancer Therapeutics

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Fighting this unconquerable mammoth of a disease that is cancer has been increasingly diffi cult from its discovery over a century ago. A multitude of agents have been identifi ed in the past to conquer the battle against cancer. Nevertheless, controlling it from its onset has been very diffi cult, the reason being its ability to evade the toxic insults, and to develop mechanisms to survive in the presence of cancer drugs. Of the several factors responsible, the phenomenon of multidrug resistance (MDR) has contributed essentially for the cancerous cells to survive. This phenomenon is characterized by the ability to impart immunity to several classes of drugs with different structural and mechanistic traits. The association of ATP-binding cassette (ABC) effl ux transporters with the development of MDR has been a major impediment toward attaining an effi cient chemotherapeutic outcome in cancer patients. Overcoming this pathway of resistance with the use of modulators to block the drug effl ux transporters has shown some promise in recent years. However, there is still room for improvement in designing the clinical strategy and developing newer agents to overcome MDR. Nature has provided researchers

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“…Since replacing the N-Me-L-phenylalanine by proline favors the synthesis of the s-cis rotamer, several proline analogues and one triamide analogue of hapalosin have been synthesized [80][81][82]. To improve the reversal effectiveness independently to cytotoxicity, hapalosin needs to be strongly modified [84]. This point was confirmed by further studies [83].…”

Section: Cyclic Peptides and Depsipeptides: Hapalosin Cryptophycins mentioning

confidence: 91%

Marine Metabolites Overcoming or Circumventing Multidrug Resistance Mediated by ATP-Dependent Transporters: A New Hope for Patient with Tumors Resistant to Conventional Chemotherapy

Barthomeuf¹,

Bourguet‐Kondracki²,

Kornprobst³

2008

ACAMC

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The treatment of chemoresistant tumors represents an important challenge in the field of oncology. Primary or acquired overexpression of ATP-dependent transporters, in particular P-glycoprotein (Pgp, MDR1 protein), is a major cause of multidrug resistance and reduced patient survival. Sustained efforts have thereby been undertaken to find agents overcoming this resistance. This review provides a chemical and biological overview on bioactive metabolites from the marine field (natural molecules and analogues) that can overcome or circumvent resistance to ATP-dependent efflux pumps, their mechanisms of action and their structure-activity relationships. Their clinical relevance and status are presented. Active compounds (often microtubule-interacting agents) have been isolated from sponges and ascidians and, in lesser extent from cnidarians, and molluscs. The toxicity and the reversal activity can be uncoupled but, marine metabolites usually maintain high toxicity in multiresistant cancer cells. Certain display synergistic effects with clinically important anticancer drugs. The marine drug recently approved for cancer therapy [Trabectedin (Yondelis)] and those entered into clinical trials act on multiple targets and, circumvent or overcome chemoresistance through very unusual mechanisms of action. Pharmacological and clinical data suggest that metabolites from the marine field could provide new therapeutic options for patients with tumors resistant to conventional therapy.

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Synthesis and evaluation of hapalosin and analogs as MDR-reversing agents

Cited by 35 publications

References 24 publications

The cyclization of peptides and depsipeptides

The cyclization of peptides and depsipeptides

ABC Transporter Modulatory Drugs from Marine Sources: A New Approach to Overcome Drug Resistance in Cancer

Marine Metabolites Overcoming or Circumventing Multidrug Resistance Mediated by ATP-Dependent Transporters: A New Hope for Patient with Tumors Resistant to Conventional Chemotherapy

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