华陀再世

The latest breast-cancer chemotherapy to hit the market is more than just a triumph for patients in desperate need of treatment. Approved by the US Food and Drug Administration on 15 November, the highly complex molecule Halaven (eribulin mesylate) is the product of nearly 25 years of struggle in the lab. It represents a hard-won victory for the total synthesis of natural products, a field of chemistry that, although still popular in academia, had gone out of fashion for many in the pharmaceutical industry.

Eribulin is a synthetic compound that mimics part of the structure of halichondrin B, a molecule found in the sea sponge Halichondria okadai. Researchers learned that halichondrin B has potent tumour-fighting activity shortly after its discovery in 1986. But it is present in very low concentrations, making it difficult to isolate. The compound also has a fiendishly complicated structure — at the time of its discovery, producing it from scratch was well beyond the abilities of chemists.

A few years later, however, organic chemist Yoshito Kishi of Harvard University in Cambridge, Massachusetts, eyed the halichondrin B structure and decided to take a crack at it. His team had little interest in its anticancer properties, he says. They were simply looking for a project to test a chemical reaction — the Nozaki–Hiyama–Kishi reaction — that could be used to build bonds between carbon atoms.

Kishi's team had set themselves an enormous challenge with halichondrin B. Natural products often contain carbon stereocentres, in which surrounding atoms can be arranged in two mirror-image configurations. "If you don't get the stereocentres set up perfectly, it generates a mixture" of different molecules that can be extremely troublesome to separate, says Ian Paterson, a chemist at the University of Cambridge, UK, who works on natural-product synthesis. Although two mirror-image forms of a molecule are indistinguishable for most chemical reactions, they can produce completely different biological effects.

Halichondrin B has a staggering 32 stereo-centres, meaning that there are 232 — more than 4 billion — possible forms, or isomers, of the molecule. "It's just ridiculous," says Robert Salomon, an organic chemist at Case Western Reserve University in Cleveland, Ohio, whose lab spent four years unsuccessfully trying to synthesize the compound in the early 1990s.

Nevertheless, Kishi's team succeeded. By the time he published a method for synthesizing the compound in 1992 (T. D. Aicher et al. J. Am. Chem. Soc. 114, 3162–3164; 1992), researchers at the Natural Products Branch of the US National Cancer Institute (NCI) in Frederick, Maryland, had discovered that halichondrin B fights cancer cells by inhibiting a protein component of the cytoskeleton — the internal latticework of rods and filaments that gives a cell its shape. That protein, called tubulin, is needed to support the rapid growth of cancer cells and is the target of several other cancer chemotherapies, including Taxol (paclitaxel).

Deep-sea drug
But Kishi's synthesis was practical for generating only small quantities of halichondrin B, unlikely to be enough to usher the compound through preclinical and then clinical testing, says David Newman, now chief of the NCI's Natural Products Branch. Newman decided that he would simply isolate the compound from natural samples. So he headed for the sea to hunt for the prized compound.

Newman and his team collected more than one tonne of Lissodendoryx, another type of sponge containing halichondrin B, from the deep waters off New Zealand. He also teamed up with researchers to grow more of the sponges, flying seaplanes out to remote aquatic farms where the sponges grew attached to lines dangling 40 metres beneath buoys. The reward for his efforts: just 300 milligrams of halichondrin B, the equivalent of a few grains of rice. "My hair turned white as a result of halichondrin B," he jokes.

Meanwhile, Tokyo's Eisai Pharmaceuticals had licensed the patent on Kishi's method and began synthesizing hundreds of analogues of the compound. Newman's haul from New Zealand was just enough to conduct comparative studies with some of these analogues. One of them, eribulin, is more potent than halichondrin B yet also substantially smaller and easier to make. But it still has 19 stereocentres (see structure), and production of eribulin on a commercial scale seemed unfathomable.

Eisai says that eribulin takes 62 steps to synthesize — a remarkably long process for a marketable drug. The company was initially apprehensive about the project, says Kishi. But once the phase I study results had shown that the drug was safe — and revealed hints of clinical efficacy — "all the reservations disappeared", he says.

Further clinical trials showed that eribulin extends the lifespan of patients with late-stage breast cancer by an average of 2.5 months in those who are not benefiting from other chemotherapies such as Taxol, also a natural-product derivative. Analysts suggest that eribulin could command a US$1-billion market if it is approved for treatment of other cancers.

Few other pharmaceutical companies have been willing to bet on complex natural products. During the 1990s, many largely abandoned natural-product chemistry, focusing more on screening large libraries of synthetic chemicals for drug candidates, says Michael Jirousek, who once worked on halichondrin B synthesis and is now chief scientific officer and co-founder of Catabasis, a biotechnology company in Cambridge, Massachusetts. "Screening natural products and isolating the active ingredients is becoming a lost art," he says.

Proponents of total synthesis point to eribulin as proof that their approach, albeit arduous, can be highly successful. Phil Baran, a synthetic chemist at the Scripps Research Institute in La Jolla, California, says that more young investigators are entering the field and that improvements in chemical techniques are making it possible to synthesize additional complex molecules by commercially viable routes. "As advances in organic chemistry become greater and greater," he says, "I think we're going to see a lot more complex compounds being pursued by companies."

英国《自然》杂志的新闻评论 http://www.nature.com/news/2010/101130/full/468608a.html


美国食品和药品监督管理局 2010年11月15日批准Halaven(eribulin mesylate)治疗转移乳癌患者对其晚期疾病曾接受至少2种既往化疗方案。

根据美国国家癌症研究所，乳癌是妇女中第二位领先的癌死亡相关原因。本年度，估计207,090妇女将被诊断有乳癌，而39,840妇女将死于该疾病。

Halaven是来自海海绵Halichondria okadai化疗活性化合物的一种合成形式。这种可注射的治疗是一种微管抑制剂，被认为通过抑制癌细胞生长起作用。接受Halaven前，患者应曾对早期或晚期乳癌接受既往基于蒽环类[anthracycline]-和紫杉烷类[taxane]-化疗。

在一项762例转移乳癌妇女对晚期疾病曾接受至少2种既往化疗方案的单独研究中确定Halaven的安全性和有效性。患者被随机赋予接受治疗用或者Halaven或被他们的肿瘤学家选择的不同的一种单药治疗。

研究被设计成测量当这种治疗开始直至患者死亡时间的长度(总生存)。接受Halaven患者中位总生存是13.1个月，与之比较接受某种单药治疗为10.6个月。

FDA的药物评价和研究中心所属肿瘤药物产品室主任Richard Pazdur, M.D.,说：“对早已接受其它治疗有侵袭型晚期乳癌妇女，治疗选择很有限。”“Halaven显示明确的生存效益和对妇女是一种重要的新选择。”

用Halaven治疗妇女报道的最常见副作用包括感染，中性白细胞减少(中性粒细胞减少)，贫血，白血细胞数减少(白细胞减少症)，毛发脱落(脱发)，疲劳，恶心，软弱(虚弱), 神经损伤(周围神经病变)，和便秘。

FDA-批准用于治疗晚期，难治性乳癌的其它治疗包括Xeloda(卡培他滨[capecitabine])对紫杉醇[paclitaxel]和蒽环类-含化疗耐药乳癌患者；Ixempra(伊沙匹隆[ixabepilone])对蒽环类，紫杉烷类和Xeloda失败后晚期疾病患者；和Ixempra加Xeloda对基于蒽环类-和紫杉烷类化疗失败后晚期疾病患者。。。